Ce numéro de Regards économiques se concentre sur divers aspects du "plan Marshall" (ci-dessous "le plan") qui ont un lien direct avec le marché du travail en Wallonie. Il les situe par rapport à son fonctionnement, par rapport à certaines politiques fédérales et à la problématique salariale en Belgique et dans ses régions. Face aux difficultés à pourvoir certains types d'emplois vacants en Wallonie et au manque simultané d'opportunités d'emploi, quels sont les remèdes ? Où le plan peut-il agir ? "Le problème de la Wallonie, c'est le manque d'offres d'emploi", entend-on dire souvent. D'un autre côté, depuis quelques années, est apparue la problématique des postes vacants difficiles à pourvoir (ou des "fonctions critiques"). Bien que la coexistence de ces deux problèmes n'ait rien de surprenant, on a de bonnes raisons de se soucier simultanément de chacun d'eux. Divers mécanismes sont à prendre en compte. Le "plan" agit sur certains d'entre eux mais doit être complété par des outils fédéraux. Le plan devrait par divers canaux stimuler à terme le nombre de postes vacants créés (renforcement de l'innovation, stimulation de la création d'activités et création de "pôles de compétitivité"). Il est trop tôt cependant pour en juger. L'essentiel dépendra de la capacité de nos institutions publiques et privées à mettre ces actions en œuvre avec efficacité. Dans ses domaines de compétence, le "plan" prévoit des mesures qui devraient favoriser la conciliation entre vie familiale et professionnelle (renforcement des capacités d'accueil de jeunes enfants et d'aide «aux personnes dépendantes» par le recrutement de près de 2000 emplois subventionnés dans le secteur non marchand). Ceci devrait faciliter l'acceptation d'une offre d'emploi. Le FOREM et des organismes privés cherchent à faciliter la rencontre entre demandeurs d'emplois et postes vacants. Le plan prévoit un renforcement des moyens du FOREM à cet égard mais uniquement en faveur des stagiaires en formation au sein du FOREM lui-même. Cette restriction est difficile à justifier. Comme les difficultés de recrutement tiennent aussi à un déficit de compétence, le "plan" prévoit un renforcement de l'effort de formation, en particulier pour les fonctions identifiées comme critiques et dans les secteurs liés aux pôles de compétitivité. Cette sélectivité apparaît cohérente. Divers instruments renforcés par le "plan" (le Plan Formation-Insertion, l'apprentissage des langues, l'enseignement en alternance) ne sont pas nouveaux. Ils ont fait parfois l'objet d'évaluations critiques. On attend des décideurs qu'ils prennent la pleine mesure des conclusions essentielles de celles-ci parallèlement à l'octroi de moyens supplémentaires. Le "plan" intègre la création d'un instrument nouveau par la Communauté française: les Centres de Technologies Avancées. Il s'agit de labelliser et de renforcer les moyens d'établissements scolaires spécialisés dans des secteurs porteurs d'emploi. Ces centres s'ajoutent à une autre structure, créée assez récemment par la Région wallonne et dénommée les Centres de compétence. Etant donné la rapidité des évolutions technologiques, l'enjeu est de taille. La sélection des projets et la coordination entre la Région et la Communauté seront ici aussi déterminants. La difficulté à pourvoir des emplois vacants est aussi liée à des facteurs non monétaires nuisibles à la qualité de l'emploi (horaires difficiles, risques d'accident de travail, etc.), au statut social associé ou non à l'emploi et aux images que l'on a de la fonction offerte (voir la récente étude du DULBEA sur ce sujet). Dans le cadre du "plan", le FOREM a récemment mis en place un "plan d'action"qui vise notamment à agir sur certains de ces aspects. Sans oublier les actions régionales dans le domaine du transport public et du logement, qui ne relèvent pas du "plan", pour promouvoir davantage une meilleure rencontre entre les emplois vacants et les demandeurs d'emploi, la Région wallonne doit en particulier s'appuyer sur les instruments suivants, qui sont essentiellement du ressort de l'Etat fédéral : On sait que les gains monétaires immédiats en cas de reprise d'emploi se sont accrus dans bien des cas entre 1999 et 2003. Ces gains paraissent toutefois demeurer fort faibles en cas de reprise d'un emploi à bas salaire et à temps partiel. Le gouvernement fédéral s'est engagé à adapter périodiquement les prestations de remplacement de revenus des salariés. Face à cela, pour éviter le développement de désincitants à la reprise d'emploi, toute modification de la (para)fiscalité devrait avoir un double souci : (a) elle devrait atteindre les catégories au bas de l'échelle des revenus du travail d'une manière immédiatement tangible pour celles-ci (via en particulier les cotisations personnelles ou le précompte professionnel); (b) cependant, on ne peut alléger la (para)fiscalité au bas de l'échelle des revenus sans un ajustement dans le même sens pour les revenus plus élevés sous peine de créer des incitations perverses qui réduiraient la base taxable. Il est possible que le plan d'activation du comportement de recherche d'emploi entraîne une augmentation de l'effort de recherche. Les évaluations sont en cours. Pour autant qu'elles stimulent effectivement l'effort de recherche d'emploi, les politiques actives rendant celui-ci plus efficace (conseillers en recherche d'emploi, ateliers de recherche active, stage de mise en situation professionnelle) peuvent stimuler une embauche durable, ainsi que l'a montré une évaluation en France. Le plan d'accompagnement des chômeurs pourrait affecter le comportement de recherche d'emploi par ce canal et pas uniquement par le contrôle qu'il exerce. Coûts salariaux et productivité : Faut-il régionaliser la formation des salaires, alléger le coût du travail ? Le "plan" n'aborde qu'incidemment la problématique du coût du travail. A-t-il tort? En soi, non, car la matière est fédérale. Cette problématique et celle de la productivité sont néanmoins en toile de fond du "plan" et de bien des débats. Nous avons donc estimé utile de consacrer un part de ce numéro à ces aspects. Sur base des récentes statistiques de l'ICN, comparés à la Wallonie, le coût salarial par personne est dans la plupart des secteurs supérieur en Flandre (en moyenne, l'écart est de 8% en 2003) mais la productivité du travail est dans la plupart des secteurs supérieure en Flandre (en moyenne, l'écart est de 14% en 2004). En combinant ces informations pour 2003, on conclut que le coût salarial par unité de valeur ajoutée est en moyenne inférieur de 4,5% en Flandre. Ces moyennes cachent néanmoins une hétérogénéité sectorielle importante. De ce constat, on peut être tenté de conclure qu'il faudrait abandonner la formation des salaires au niveau (interprofessionnel et sectoriel) fédéral au profit d'une négociation à un niveau régional ou local. Ceci devrait conduire à une meilleure prise en compte des conditions locales du marché du travail lors de la négociation salariale. Nous émettons des doutes sur l'efficacité d'une telle approche. Il est bien établi que les salaires réagissent faiblement au niveau du chômage en Belgique. Rien ne permet de penser qu'une forme de régionalisation modifierait l'ampleur de cette saine réaction. Plus fondamentalement, les résultats d'une négociation se jugent par comparaison aux résultats obtenus par d'autres négociations salariales. Si donc on découpe les commissions paritaires nationales en commissions (sous-)régionales, on doit s'attendre à un effet de comparaison très puissant entre les ex-membres de la même commission nationale. Une régionalisation des négociations est alors moins efficace du point de vue de l'emploi qu'une négociation nationalequi prend en compte les spécificités régionales. Ceci est vrai tant pour la Flandre que pour les autres régions. Sans être le seul facteur pertinent (voir notamment le numéro 41 deRegards économiquesrelatif à la fiscalité), le coût du travail est un facteur central pour les régions belges. Outre le ciblage inadéquat des allégements structurels (fédéraux) de cotisations patronales de sécurité sociale, nous rappelons que des subventions temporaires à l'embauche présentent une efficacité du point de vue de l'insertion en emploi pour autant que le ciblage soit adéquat et la durée de subvention courte (un an devrait être un ordre de grandeur). La région wallonne a de longue date privilégié une autre option : les créations directes et/ou la subvention forte et durable d'emplois réservés aux chômeurs. Le "plan" prolonge cette option par le subventionnement de 2000 emplois supplémentaires (voir point b ci-dessus). Les secteurs bénéficiaires – dans une large mesure les secteurs publics et non-marchand – reçoivent ainsi un soutien parfois essentiel. Il nous apparaît que cette dernière motivation domine en pratique. Nous ne voyons donc pas les raisons de réserver ces emplois à des personnes disposant de statuts spécifiques – souvent complexes à définir. Que faut-il faire et, surtout, ne pas faire en matière d'évaluation des politiques d'emploi? L'enjeu de l'évaluation est proclamé de plus en plus souvent, en particulier par le "plan". Mais est-on bien conscient de ce que "évaluer" veut dire? Nous sommes convaincus du contraire. Le «nombre de contrats signés», le «nombre de bénéficiaires», le «parcours des bénéficiaires sur le marché du travail» et même une comparaison grossière entre ces parcours et ceux d'un vague groupe de contrôle sont autant d'indicateursdescriptifsintéressants. Ils ne permettent cependantpasde se prononcer sur l'effet du dispositif sur les chances d'insertion des demandeurs d'emploi. Des méthodes plus sophistiquées et plus fiables existent mais elles ne s'improvisent pas. Elles requièrent du temps et un savoir-faire pointu. Nous préconisons donc ceci: Il y a lieu de penser l'évaluation d'un programme avant même son lancement. Il faudrait interdire le lancement d'une nouvelle politique avant que le processus d'évaluation n'ait été défini et reconnu pertinent par une instance indépendante. L'Institut Wallon de l'Evaluation, de la Prospective et de la Statistique (IWEPS) doit être doté de moyens substantiellement plus importants pour qu'il puisse notamment mener à bien ses missions d'évaluation.
Cette recherche a été menée dans la région des Hauts-de-France, avec la collaboration d'un service d'AEMO du département du Nord pour la partie qualitative et des services du département du Nord et du Pas-de-Calais pour sa partie quantitative. Dans un premier temps, l'étude quantitative dresse les principales caractéristiques des mesures de « Tiers Digne de Confiance » (TDC) prononcés par les juges en comparant celles associées à une mesure d'action éducative en milieu ouvert (AEMO) et celles non associées à une AEMO. D'après les données de la DREES, les mesures de TDC correspondent à 7% des placements. L'analyse de la base de données permet de mettre en évidence que dans le département du Nord (870 mesures au 31 décembre 2014), les mesures de TDC sont accompagnées une fois sur deux d'une AEMO. Entre les groupes de mesures TDC avec AEMO versus sans AEMO, il n'y a pas de différence significative selon le sexe. La distribution de l'âge des enfants placés chez un TDC et faisant l'objet d'une AEMO se rapproche de celle de l'ensemble des enfants en protection de l'enfant dans la région, tandis que celle des enfants seulement concernés par le fait d'être confié à un tiers présente la particularité de concerner davantage d'adolescents de 15 à 17 ans. Même s'ils ne rendent pas compte de l'ensemble des mesures, deux types de situations peuvent se distinguer parmi les mesures de TDC. D'une part des mesures concernant des adolescents dont c'est la première rencontre avec le système de protection de l'enfance, d'autre part des situations ressemblant à l'ensemble des mesures de protection de l'enfance dans la région : commençant tôt dans l'enfance, se poursuivant sous différentes formes dont ici, celle du placement chez un TDC. L'étude qualitative a été réalisée entre juin 2014 et septembre 2016. Elle concerne les enfants confiés à un proche et faisant l'objet d'une Action Educative en Milieu Ouvert (AEMO). Seules 4 des 30 situations correspondent à un arrangement à l'amiable entre les membres de la parenté. La plupart des interventions portées à notre connaissance (26/30) sont des mesures prononcées par le juge qui attribue au(x) membre(s) de la parenté le statut de TDC.Cette étude montre que ce sont plus souvent les femmes qui sont désignées TDC, même lorsqu'il s'agit de l'accueil par un couple. Les tiers sont de condition modeste même si le tiers appartient généralement à la moins dépourvue des familles maternelle ou paternelle. Les grands-parents sont le plus souvent désignés comme tiers digne de confiance avec un équilibre entre l'implication des deux lignées, ce qui diffère des études précédentes. De plus, le sexe de l'enfant n'intervient pas dans une hypothétique attribution privilégiée à l'une ou l'autre des familles.Si l'on considère les enfants issues de la mère, l'enfant confié à un proche est plus souvent un aîné. Par ailleurs, les fratries (issues d'une même mère) sont très souvent touchées simultanément par d'autres formes de placement en famille d'accueil ou en établissement. Nous avons constaté que, contrairement à d'autres études, les enfants étaient majoritairement placés chez un proche avant l'âge de 10 ans et pour des durées conséquentes. Au début de notre étude, ¼ des enfants vivait chez le proche depuis au moins 6 ans. Conformément à l'approche quantitative présentée au début de ce rapport, l'étude montre qu'à côté de quelques placements survenant durant l'adolescence, la plupart des enfants concernés par notre recherche sont des enfants placés relativement tôt et pour des durées longues en rapport avec les problématiques complexes, souvent rencontrées en protection de l'enfance. Les rares adolescentes [Clémentine (1), Mélia (17), Claire et Coralie (23)] dont la mesure commence tardivement, font cependant d'emblée l'objet d'une mesure d'AEMO associée au fait d'être confiées à un proche, en raison soit d'une situation très vive de rupture et de violence conjugales (1), soit de problématiques complexes (meurtre et emprisonnement du père (17), inceste révélé par les adolescentes (23)). Le choix d'entrer sur le terrain par le service d'AEMO ne permet pas de rejoindre des adolescents faisant l'objet d'un placement chez un proche sans mesure d'AEMO, situations dont l'étude quantitative laissait entrevoir l'existence. Les proches soulignent que c'est souvent leur premier contact avec les services sociaux, que les premières audiences sont particulièrement stressantes, qu'ils connaissent peu leurs droits et devoirs et qu'ils découvrent les attributs des différents professionnels de la protection de l'enfance. Lorsque nous les avons rencontrés, ils ont bien intégré les préoccupations des travailleurs sociaux sur le respect des places de chacun. Aussi, insistent-ils sur le fait qu'ils ne sont pas les parents. Ils font régulièrement référence au travail parental qu'ils effectuent et à la « bonne distance » qu'ils préservent. La question des places et de la substitution des parents, et particulièrement de la mère, est un point auquel veillent les professionnels de la protection de l'enfance. Ces questions se retrouvent fréquemment dans les travaux sur les familles d'accueil. Cependant il semble que cette surveillance soit encore plus attentive lorsque la personne en charge de l'enfant est un membre de la parenté.L'importance des situations de précarité pose avec acuité la question du soutien financier aux proches accueillants. Dans ce contexte, le lecteur s'étonnera que l'allocation d'entretien ne soit pas systématiquement versée, dès lors que le juge des enfants a désigné le tiers, ou encore qu'une démarche systématique et proactive ne soit entreprise en ce sens par les services sociaux, (il conviendrait de définir à qui reviendrait cette tâche en cas d'une part, de mesure simultanée d'AEMO et d'autre part, en son absence). En effet, pour certaines situations, le travail éducatif des proches est doublement gratuit : il n'entraîne pas de salaire, et n'ouvre pas systématiquement à un dédommagement des frais. Ajoutons à cela les hésitations des travailleurs sociaux à modifier le nom du bénéficiaire des allocations familiales, de peur de mettre symboliquement le parent, un peu plus sur la touche. Au total, comme dans les études anglaises, les problèmes matériels du proche ne sont sans doute pas considérés à leur juste mesure. Actuellement, il faut que le proche lise attentivement le jugement et entreprenne de lui-même les démarches auprès du conseil départemental. Prendre cette initiative est d'autant plus coûteux que les proches acceptent ce statut, mus par une obligation morale, avec le sentiment de devoir tout faire pour éviter un placement hors de la parenté. Tenus par cette obligation morale, ils peuvent ressentir un certain malaise à réclamer des contreparties à cet engagement. Dans le même ordre d'idée, compte tenu de la précarité des familles concernées et du manque d'information sur le statut du tiers et de l'enfant confié, il serait sans doute opportun que les possibilités d'aides aux jeunes majeurs soient davantage portées à la connaissance des familles. Dans les cas parvenus à la majorité en cours d'étude, la mesure s'est interrompue et il ne nous a pas été possible d'entrer en contact avec ces familles. Cet arrêt brutal confirme les données quantitatives qui mettaient en évidence un très faible nombre de maintien dans la protection après la majorité pour les enfants placés chez un tiers digne de confiance. D'autre part, le travail de Sarah Mosca auprès des familles a mis en évidence que le rôle du proche s'exerce au sein d'un réseau familial de proximité, peu connu des intervenants sociaux. Il s'inscrit dans la durée et bien souvent précède le placement. Ce point avait déjà été constaté en Angleterre, mais le présent travail a pu compléter cette information en observant que ce soutien bénéficie souvent aussi bien au(x) parent(s) qu'à l'enfant, ce qui n'exclut pas des mésententes entre le(s) grand(s)-parent(s) et le(s) parent(s) de l'enfant. Par ailleurs, les entretiens avec les travailleurs sociaux ont montré que ce soutien se prolonge dans les moments de retour de l'enfant auprès du/des parent(s). Les travailleurs sociaux regardent cette continuité avec pragmatisme tout en s'interrogeant sur les raisons qui mobilisent les proches. Les proches s'organisent pour accueillir, présentent seuls ou avec l'aide de l'entourage l'enfant aux visites en lieu neutre ou médiatisé, s'accommodent des tracasseries administratives engendrées par une situation rare et floue, pourvoient aux besoins de l'enfant, s'entourent du soutien dont ils ont besoin en faisant appel aux membres de la parenté vivant à proximité, mais tant d'engagement conduit souvent au doute des professionnels : pourquoi font-ils tout cela ? Les travailleurs sociaux oscillent donc entre la recherche de motivations inavouées et le fait de saisir l'opportunité d'une solution qui, le plus souvent, a déjà fait ses preuves avant la crise. Cependant, dès qu'un père ou une mère exprime son souhait de présence auprès de l'enfant, et conformément au paradigme français en protection de l'enfance qui privilégie le retour chez le(s) parent(s), le filet de sécurité que les proches ont tissé autour l'enfant cède le pas au désir du parent et retourne à son statut informel. Il faut organiser des rencontres, établir un lien qui n'a parfois jamais existé, au risque d'insécuriser le proche et l'enfant. Si le parent n'a pas assumé son rôle depuis de nombreux mois, s'il n'a pas donné signe de vie à l'enfant et à son entourage, s'il ne s'est pas inquiété de lui, fusse à distance, il peut néanmoins surgir à tout moment. D'une certaine manière, les devoirs du parent à l'égard de l'enfant semblent pouvoir s'exercer de manière discontinue sans que cela remette en cause la totalité de ses droits. Cette étude pose une question commune à tous les dispositifs de suppléance parentale : comment établir ou maintenir une forme de parentalité sans aggraver la discontinuité des parcours ? La pluriparentalité, concept qui entrevoit la possibilité de plusieurs figures d'attachement non concurrentielles semble avoir bien du mal à s'imposer en France. Lorsqu'on prend en compte l'obsession de ne pas prendre la place du parent, tout en assumant les fonctions, tant dans les discours des travailleurs sociaux que des proches, on mesure combien la pluriparentalité est un impensé de la protection de l'enfance pour l'ensemble de ses acteurs quotidiens.Comme cela a été relevé par Hunt dans ses travaux, les proches souhaitent avoir l'occasion de parler entre pairs ou avec un interlocuteur différent de la personne en charge de la mesure pour l'enfant. En effet, face à l'éducateur d'AEMO mandaté pour assurer des relations satisfaisantes entre le tiers et le parent, face à la fragilité du dispositif qui met en avant le droit du parent sans en garantir pour le proche, l'expression des difficultés réelles ou subjectives auprès de l'éducateur est perçue comme pouvant desservir la poursuite de la garde. L'éducateur d'AEMO est bien identifié comme servant l'intérêt de l'enfant et la régulation des conflits. En conséquence, il n'apparaît pas comme un intervenant neutre susceptible de soutenir le proche à part entière.Enfin à l'issue de cette étude, une question reste posée : est-ce que la recherche d'un proche susceptible d'accueillir l'enfant est entreprise de manière systématique lorsqu'il apparaît aux travailleurs sociaux qu'il serait nécessaire d'avoir recours à un placement ? Avec les nouvelles possibilités ouvertes par la loi du 14 mars 2016, cette question sera sans doute à l'ordre du jour dans les mois à venir. La présente étude tire les leçons de l'expérience des parents et des professionnels de cas jusqu'ici rencontrés dans le cadre juridique.
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Do Spew and 2 rhyme? I sure hope so as I begin my review of the year that was. The last time I blogged less than I did in 2022 was ... in 2008, when I didn't blog at all. What explains the decline? Partly exhaustion, partly a decline in imagination, partly other social media sucking up my time (the podcasts, now tooting as well as tweeting), and partly the reality that I have written enough stuff before that when the topic comes up, it is just easier to repost. Maybe a look at this year's posts will tell me a bit about what inspires me to write here and what does not, although survivor and recency biases may mesh nicely with my confirmation bias to prevent me from learning that much. Hmmm.JanuaryI started by pondering whether JK Rowling has utterly destroyed her legacy--whether I can still consume Harry Potter stuff. While I concluded that I could still enjoy the world she created, even as she betrays damn near all of it, my behavior, my choices, says otherwise as I had multiple opportunities to watch HP movies while hanging out at my mother-in-law's over the holidays and dodged all of them. Something I had not done in the past. Later in the month, I returned to the theme of what kinds of stuff can I read and enjoy given the complex realities of our time. I wrote about how it has become harder to watch and read cop shows given what we know about cops these days. I am finishing the latest John Sandford book which features multiple cops, Virgil Flowers and Lucas Davenport, solving a serial murder spree by bitcoin assholes, and have found it fairly compelling (unlike the most recent Jack Reacher book). So, maybe I am less affected by the topics than by the behavior of the artist?The month ended with the start of the occupation of Ottawa by extremists--far right white supremacists. The year ended with an examination of whether the government should have invoked the Emergency Act. Um, yeah, but because the emergency was that the provincial leaders were cowards who wanted the feds to own it.FebruaryThe extremists in Ottawa became a focus for me, as it did for most of my city, for most of the month with posts on: outbidding, explaining why the Conservatives were pandering to the extremistsanger, discussing how pissed off this made me, triggered indeed.policing, as I learned that Canadians think that the cops should not be directed by the politicians as if policing is not inherently political,my take on the Emergency Act.And then the past came back to bite Ukraine and me. My previous work on irredentism became relevant again with Russia's invasion of yet more Ukrainian territory. In this post, I explained the basics of irredentism--that it is always bad for the country doing the invading even as it may or may not be bad for its leader, that domestic dynamics are key, and so on.March The focus of March was very much on the war in Ukraine. I argued via a bit of screenwriting why a No Fly Zone was a bad idea. I elaborated about the disease of MOAR. And, yes, I then invoked my work on irredentism to explain why Putin was willing to kill Russia's kin in order to "save" them. I wrote about limited war, a topic that got new energy this week as some retired generals expressed much frustration at the unwillingness of the US to send deep strike weapons to Ukraine.I also blogged about my appearance before the House of Commons Defence Committee.AprilThis month had only a few posts, with nearly all focused on CDSN events. The outlier was a post discussing the appearance of Minister of National Defence Anita Anand in my Civil-Military Relations class. That was super-cool--a great way to finish off that course.MayI marked my 300,000th tweet before twitter's death spiral... maybe I caused it?I discussed the two events organized by the CDSN Undergraduate Excellence Scholars--a conference and a hackathon. I also went to Germany for another conference. Woot!My last post took a first look at the Arbour report, where a retired Supreme Court Justice assessed the Canadian Armed Forces and why it has fallen short, yet again, on reforming itself when it comes to sexual misconduct. I took a quick tour of the 48 recommendations. June I didn't write much in June, but two of my posts continued my examination of the Arbour Report: here and here. In the first one, I pushed on a point that will become a key question in my next project--what is the proper rule of a defence department or ministry or agency? Arbour says DND is to support the CAF, and, no, nope, nuh uh. This does help to explain a big problem with this and previous reports--having a very limited view of what DND's job is. I also focus on the lack of a recommendation for an Inspector General, which is now a topic of research of this year's Visiting Defence Fellow.I also marked my 10 years in Ottawa with this post. I am so glad that the tides of the academic job market washed me ashore here. It was not my plan, but it has worked out wonderfully.JulyJuly was a month of ups and downs. I started the month by pondering how long might the autocratic moment in the US last if Democracy were to give way. The most pivotal building at my old summer camp burned down, but there was much resilience that day and beyond to give me hope for its future.One of the ups was the new season of Battle Rhythm. I am forever grateful to Stéfanie von Hlatky for helping us launch our podcast, and I was sad to see her move to admin stuff at her university. But we got re-energized by a new crew of co-hosts. Artur, Anessa, Erin, and Linna have provided a variety of perspectives since they joined us. I am most grateful to Melissa Jennings for doing most of the heavy lifting in this effort and to Carelove Doreus and Racheal Wallace for their carrying the rest of the load. It has been a big year in Canadian civil-military relations, and one of the highlights was the decision to adjust the uniform standards to make the CAF more welcoming to more people. I addressed these changes with some accidental foreshadowing of the awful Vimy speech by one of those responsible for the culture crisis that prevented the CAF from adapting sooner.The month, which started with COVID finally hitting me and Mrs. Spew thanks to a conference trip to Berlin, ended in an upswing with both Beulahfest as my mom celebrated her 90th birthday and, yes, Stevefest, as I did a heap of stuff to celebrate another year of me. AugustNot many posts this month as I was very busy organizing and then hosting the first in-person CDSN Summer Institute. It was one of the original ideas animating the big grant application, and it was great to see it finally come to fruition with so many sharp people speaking and participating. Plus it was an excuse to have a reception or three. Just a great week worth all the effort by the CDSN team.Much news about classified documents thanks to Trump hoarding documents he should have had anymore, so I shared what I had learned during the year I had a top secret clearance and worked every day in a SCIF--secure compartmented information facility.Finally, I said goodbye to a key part of my life--ultimate frisbee. I just kept getting injured and could not stay on the field. I could still throw well, but that whole running thing proved to be too much. I very much miss it, it gave me friends across North America, it gave me some level of fitness, it gave me heaps of silliness, and nothing can fill the hole it left behind, alas. SeptemberAnother light month for blogging. I wrote a guide for those visiting Montreal for the American Political Science Association meeting. The focus of the month and of my career these days was/is civil-military relations. I wrote about the retired generals and SecDefs providing advice on how to manage this relationship. And then I addressed a recurring challenge up here--should the Canadian military prioritize domestic emergency operations? Whether the CAF wants to or not (not), climate change is going to make this happen. It already has. I am getting more and more interested in studying domestic emergency ops in part because few defence scholars have done so. Nothing like having a wide open field to pass the disk into. Oh wait, that was last month's post about ultimate.One reason I didn't post more in September is that I was headed west to Disneyland and to visit my daughter (not necessarily prioritized that way?).OctoberI gave thanks for all kinds of stuff as Canada celebrates Thankgiving in October when Americans debate the role of Columbus.I spent the rest of the month preparing both the CDSN Midterm Report for one of our funders and a conference to mark the midway point in our SSHRC grant. It was great to hear from the co-directors of the various research efforts--Civ-Mil Relations, Personnel, Security, and Operations. We were once told that the CDSN was just me and my friends dong stuff, but, to be clear, when it started, many of those who joined as co-directors were not friends and some were barely acquaintances. Now, we are friends, but isn't that how networking works when it works well? I am very proud of what we have put together even if it put a major dent in my blogging.November Was the theme of the month commenting on other people's mistakes? Seems like it with a post on twitter's dramatic decline thanks to Musk and then the craptastic speech by a retired general. That post generated more hits than any other this year and is in the top five of my 13 years of blogging. The related tweet was also the most tweeted/impressioned tweet of the year and then some. It led to a post addressing "woke" and being "anti-woke," which helped me think about vice-signaling, the flipside of virtue-signaling. I got to put on my old NATO hat when some errant missiles from Ukraine's war with Russia landed in Poland. I did much media as well to explain that NATO does not work the way may folks think--that there is nothing automatic about it, even if the attack had been deliberate.One reason I blog less is that I simply have not been writing that much about pop culture here. Why? Mostly due to lack of time. One exception to this was thinking about the International Politics of the second Black Panther movie.DecemberThe year ended with much CDSN and much cookies!I went to Winnipeg for the first time for a CDSN workshop on Domestic Emergency Operations. This is the focus of one of our four MINDS (DND) funded research projects. I learned a great deal from sharp people both in and out of the government. There is much work to do here, and I am glad we have made this one of our foci over the next three years. Once again, we held an end of the year conference, the Year Ahead, which addresses some of the issues on the horizon. This year, we also launched the new CDSN Podcast Network at the event! The CDSN Podcast Network brings together four podcasts--Battle Rhythm, Conseils de Sécurité, SecurityScape and NATO Field Report. We are open to adding others down the road. Along the way, we fixed our Apple podcast feed. I am most excited not just for having a new home for BattleRhythm but connecting and amplifying some student-run podcasts.I finished the year with a heap of baking--cookies for friends around Ottawa. The basic idea is this: I want to eat a lot of different kinds of cookies. But then making so many different kinds means finding people who are willing to take most off my hands or else I will gain a heap of weight (winterfest did that anyway). I enjoyed my first cookiefest in 2020, which was the first time I saw many people after months and months of quarantining. So, I keep doing it, now armed with better equipment (kitchen aid stand mixer makes it much easier than the first cookie fest) and more recipes. It is not just the baking and the eating. I got to chat with a bunch of great people as I delivered the cookies. If the cookies are joy (and, yes, they are), giving joy leads to receiving much joy.One of the interesting dynamics of 2022 was the re-emergence of blogging. That many folks started writing on substack, which, to me, seems like blogging but with the chance of income. I have not moved over there as I am pretty happy with this perch. It does not make me money, but I doubt that people would pay that much for my half-baked (semi-spewed) writings. One of my New Year's Resolutions is to blog more. My guess is that I will be more successful at that than the ones focused on dietary restraint.May you and yours have a terrific 2023!
HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples. ; 3C. Three-City Study. The work was made possible by the participation of the control subjects, the patients, and their families. We thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. The 3C Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM "Cohortes et collections de données biologiques" programme. Lille Génopôle received an unconditional grant from Eisai. AGES. Age, Gene/Environment Susceptibility-Reykjavik Study. This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC. Atherosclerosis Risk in Communities study. The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. This work as well as YL and AK were supported by the German Research Foundation (KO 3598/2-1, KO 3598/3-1 and CRC1140 A05 to AK). ASPS. Austrian Stroke Prevention Study. The research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS. The authors thank the staff and the participants of the ASPS for their valuable contributions. We thank Birgit Reinhart for her long-term administrative commitment and Ing Johann Semmler for the technical assistance at creating the DNA-bank. BMES. Blue Mountains Eye Study. The BMES has been supported by the Australian RADGAC grant (1992- 94) and Australian National Health & Medical Research Council, Canberra Australia (Grant Nos: 974159, 211069, 991407, 457349). The GWAS studies of Blue Mountains Eye Study population are supported by the Australian National Health & Medical Research Council (Grant Nos: 512423, 475604, 529912) and the Wellcome Trust, UK (2008). EGH and JJW are funded by the Australian National Health & Medical Research Council Fellowship Schemes. CILENTO. Italian Network on Genetic Isolates – Cilento. We thank the populations of Cilento for their participation in the study. The study was supported by the Italian Ministry of Universities and CNR 36 (PON03PE_00060_7, Interomics Flagship Project), the Assessorato Ricerca Regione Campania, the Fondazione con il SUD (2011-PDR-13), and the Istituto Banco di Napoli - Fondazione to MC. COLAUS. The CoLaus authors thank Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey and Sylvie Mermoud for data collection. The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, the Swiss National Science Foundation (33CSCO- 122661, 3200BO-111361/2, 3100AO-116323/1, 310000-112552). The computations for CoLaus imputation were performed in part at the Vital-IT center for high performance computing of the Swiss Institute of Bioinformatics. We thank Vincent Mooser for his contribution to the CoLaus study. EGCUT. Estonian Genome Center University of Tartu. EGCUT received financing from FP7 grants (278913, 306031, 313010) and targeted financing from Estonian Government (SF0180142s08). EGCUT studies were covered from Infra-structure grant no. 3.2.0304.11-0312 funded mostly by the European Regional Development Fund, Center of Excellence in Genomics (EXCEGEN) and University of Tartu (SP1GVARENG). We acknowledge EGCUT technical personnel, especially Mr V. Soo and S. Smit. Data analyses were carried out in part in the High Performance Computing Center of the University of Tartu. FamHS. Family Heart Study. The FHS work was supported in part by NIH grants 5R01HL08770003, 5R01HL08821502 (Michael A. Province) from the NHLBI and 5R01DK07568102, 5R01DK06833603 from the NIDDK (I.B.B.). The authors thank the staff and participants of the FamHS for their important contributions. FHS. Framingham Heart Study. This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. GENDIAN. GENetics of DIAbetic Nephropathy study. The support of the physicians, the patients, and the staff of the Diabetes Zentrum Mergentheim (Head: Prof. Dr. Thomas Haak), the diabetes outpatient clinic Dr Nusser - Dr Kreisel, the dialysis centers KfH Amberg, KfH Bayreuth, KfH Deggendorf, KfH Donauwörth, KfH Freising, KfH Freyung, KfH Fürth, KfH Hof, KfH Ingolstadt, KfH Kelheim, KfH München Elsenheimerstraße, KfH München-Schwabing, KfH Neumarkt, KfH Neusäß, KfH Oberschleißheim, KfH Passau, KfH Plauen, KfH Regensburg Günzstraße, KfH Regensburg Caritas-Krankenhaus, KfH Straubing, KfH Sulzbach-Rosenberg, KfH Weiden, Dialysezentrum Augsburg Dr. Kirschner, Dialysezentrum Bad Alexandersbad, KfH Bamberg, Dialysezentrum Emmering, Dialysezentrum Klinikum Landshut, Dialysezentrum Landshut, Dialysezentrum Pfarrkirchen, Dialysezentrum Schwandorf, Dr. Angela Götz, the medical doctoral student Johanna Christ and the Study Nurse Ingrid Lugauer. The expert technical assistance of Claudia Strohmeier is acknowledged. Phenotyping was funded by the Dr. Robert PflegerStiftung (Dr Carsten A. Böger), the MSD Stipend Diabetes (Dr Carsten A. Böger) and the University Hospital of Regensburg (intramural grant ReForM A to Dr. A. Götz, ReForM C to Dr. Carsten Böger). Genome-wide genotyping was funded by the KfH Stiftung Präventivmedizin e.V. (Dr. Carsten A. Böger, Dr. Jens Brüning), the Else Kröner-Fresenius-Stiftung (2012_A147 to Dr Carsten A. Böger and Dr Iris M. Heid) and the University Hospital Regensburg (Dr Carsten A. Böger). Data analysis was funded by the Else 37 Kröner-Fresenius Stiftung (Dr. Iris M. Heid and Dr. Carsten A. Böger: 2012_A147; Dr. Carsten A. Böger and Dr. Bernhard K. Krämer: P48/08//A11/08). GENDIAN Study Group: Mathias Gorski, Iris M. Heid, Bernhard K. Krämer, Myriam Rheinberger, Michael Broll, Alexander Lammert, Jens Brüning, Matthias Olden, Klaus Stark, Claudia Strohmeier, Simone Neumeier, Sarah Hufnagel, Petra Jackermeier, Emilia Ruff, Johanna Christ, Peter Nürnberg, Thomas Haak, Carsten A. Böger. HABC. Health Aging and Body Composition Study. The HABC study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. HCS. Hunter Community Study. The University of Newcastle provided $300,000 from its Strategic Initiatives Fund, and $600,000 from the Gladys M Brawn Senior Research Fellowship scheme; Vincent Fairfax Family Foundation, a private philanthropic trust, provided $195,000; The Hunter Medical Research Institute provided media support during the initial recruitment of participants; and Dr Anne Crotty, Prof. Rodney Scott and Associate Prof. Levi provided financial support towards freezing costs for the long-term storage of participant blood samples. The authors would like to thank the men and women participating in the HCS as well as all the staff, investigators and collaborators who have supported or been involved in the project to date. A special thank you should go to Alison Koschel and Debbie Quain who were instrumental in setting up the pilot study and initial phase of the project. HPFS. Health Professionals Follow-Up Study. The NHS/HPFS type 2 diabetes GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033; National Institute of Dental & Craniofacial Research: U01DE018993, U01DE018903) funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease"(HHSN268200782096C). Additional funding for the current research was provided by the National Cancer Institute (P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845). We thank the staff and participants of the NHS and HPFS for their dedication and commitment. INGI-CARLANTINO. Italian Network on Genetic Isolates – Carlantino. We thank Anna Morgan and Angela D'Eustacchio for technical support. We are grateful to the municipal administrators for their collaboration on the project and for logistic support. We thank all participants to this study. INGI-FVG. Italian Network on Genetic Isolates – Friuli Venezia-Giulia. We thank Anna Morgan and Angela D'Eustacchio for technical support. We are grateful to the municipal administrators for their collaboration on the project and for logistic support. We thank all participants to this study. 38 INGI-VAL BORBERA. Italian Network on Genetic Isolates – Val Borbera. We thank the inhabitants of the Val Borbera who made this study possible, the local administrations and the ASL-Novi Ligure (Al) for support. We also thank Clara Camaschella for data collection supervision and organization of the clinical data collection, Fiammetta Vigano` for technical help and Corrado Masciullo for building the analysis platform. The research was supported by funds from Compagnia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy and Ministry of Health, Ricerca Finalizzata 2008 and 2011/2012, CCM 2010, PRIN 2009 and Telethon, Italy to DT. IPM. Mount Sinai BioMe Biobank Program. The Mount Sinai BioMe Biobank Program is supported by The Andrea and Charles Bronfman Philanthropies. KORA-F3 and F4. The genetic epidemiological work was funded by the NIH subcontract from the Children's Hospital, Boston, US, (H.E.W., I.M.H, prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (H.E.W. 01GS0823; WK project A3, number 01GS0834), the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and by the Else KrönerFresenius-Stiftung (P48/08//A11/08; C.A.B., B.K.K; 2012_A147 to CAB and IMH.). The Genetic Epidemiology at the University of Regensburg received financial contributions from the BMBF (01ER1206 and 01ER1507). The kidney parameter measurements in F3 were funded by the Else Kröner-FreseniusStiftung (C.A.B., B.K.K.) and the Regensburg University Medical Center, Germany; in F4 by the University of Ulm, Germany (W.K.). Genome wide genotyping costs in F3 and F4 were in part funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). De novo genotyping in F3 and F4 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research and by the State of Bavaria. Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum München. The LINUX platform for computation were funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center. LIFELINES. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines, and all the study participants. Lifelines group authors: Behrooz Z Alizadeh1 , H Marike Boezen1 , Lude Franke2 , Pim van der Harst3 , Gerjan Navis4 , Marianne Rots5 , Harold Snieder1 , Morris Swertz2 , Bruce HR Wolffenbuttel6 and Cisca Wijmenga2 1. Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands 2. Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands 3. Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands 4. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands 5. Department of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands 6. Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands MESA. Multi-Ethnic Study of Atherosclerosis. University of Washington (N01-HC-95159),Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University 39 (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC- 95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL- 071205) MICROS. Microisolates in South Tyrol study. We owe a debt of gratitude to all participants. We thank the primary care practitioners R. Stocker, S. Waldner, T. Pizzecco, J. Plangger, U. Marcadent and the personnel of the Hospital of Silandro (Department of Laboratory Medicine) for their participation and collaboration in the research project. In South Tyrol, the study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). NESDA. The Netherlands Study of Depression and Anxiety. The infrastructure for the NESDA study is funded through the Geestkracht programme of the Dutch Scientific Organization (ZON-MW, grant number 10-000-1002) and matching funds from participating universities and mental health care organizations. Genotyping in NESDA was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health. NHS. Nurses' Health Study. The NHS/HPFS type 2 diabetes GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033; National Institute of Dental & Craniofacial Research: U01DE018993, U01DE018903) funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease"(HHSN268200782096C). The NHS renal function and albuminuria work was supported by DK66574. Additional funding for the current research was provided by the National Cancer Institute (P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845). We thank the staff and participants of the NHS and HPFS for their dedication and commitment. NSPHS. The Northern Swedish Population Health Study. The NSPHS was supported by grants from the Swedish Natural Sciences Research Council, the European Union through the EUROSPAN project (contract no. LSHG-CT-2006-018947), the Foundation for Strategic Research (SSF) and the Linneaus Centre for Bioinformatics (LCB). We are also grateful for the contribution of samples from the Medical Biobank in Umeå and for the contribution of the district nurse Svea Hennix in the Karesuando study. RS-I. The Rotterdam Study. The GWA study was funded by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Dr Michael 40 Moorhouse, Marijn Verkerk, and Sander Bervoets for their help in creating the GWAS database. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are very grateful to the participants and staff from the Rotterdam Study, the participating general practitioners and the pharmacists. We would like to thank Dr. Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G, for access to their grid resources. Abbas Dehghan is supported by NWO grant (vici, 918-76-619). SAPALDIA. Swiss Study on Air Pollution and Lung Diseases in Adults. The SAPALDIA Team: Study directorate: T Rochat (p), NM Probst Hensch (e/g), N Künzli (e/exp), C Schindler (s), JM Gaspoz (c) Scientific team: JC Barthélémy (c), W Berger (g), R Bettschart (p), A Bircher (a), O Brändli (p), C Brombach (n), M Brutsche (p), L Burdet (p), M Frey (p), U Frey (pd), MW Gerbase (p), D Gold (e/c/p), E de Groot (c), W Karrer (p), R Keller (p), B Martin (pa), D Miedinger (o), U Neu (exp), L Nicod (p), M Pons (p), F Roche (c), T Rothe (p), E Russi (p), P Schmid-Grendelmeyer (a), A Schmidt-Trucksäss (pa), A Turk (p), J Schwartz (e), D. Stolz (p), P Straehl (exp), JM Tschopp (p), A von Eckardstein (cc), E Zemp Stutz (e). Scientific team at coordinating centers: M Adam (e/g), C Autenrieth (pa), PO Bridevaux (p), D Carballo (c), E Corradi (exp), I Curjuric (e), J Dratva (e), A Di Pasquale (s), E Dupuis Lozeron (s), E Fischer (e), M Germond (s), L Grize (s), D Keidel (s), S Kriemler (pa), A Kumar (g), M Imboden (g), N Maire (s), A Mehta (e), H Phuleria (exp), E Schaffner (s), GA Thun (g) A Ineichen (exp), M Ragettli (e), M Ritter (exp), T Schikowski (e), M Tarantino (s), M Tsai (exp) (a) allergology, (c) cardiology, (cc) clinical chemistry, (e) epidemiology, (exp) exposure, (g) genetic and molecular biology, (m) meteorology, (n) nutrition, (o) occupational health, (p) pneumology, (pa) physical activity, (pd) pediatrics, (s) statistics. Funding: The Swiss National Science Foundation (grants no 33CSCO-134276/1, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO- 104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099), the Federal Office for Forest, Environment and Landscape, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, the Swiss Lung League, the canton's Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais and Zurich, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA. The study could not have been done without the help of the study participants, technical and administrative support and the medical teams and field workers at the local study sites. Local fieldworkers : Aarau: S Brun, G Giger, M Sperisen, M Stahel, Basel: C Bürli, C Dahler, N Oertli, I Harreh, F Karrer, G Novicic, N Wyttenbacher, Davos: A Saner, P Senn, R Winzeler, Geneva: F Bonfils, B Blicharz, C Landolt, J Rochat, Lugano: S Boccia, E Gehrig, MT Mandia, G Solari, B Viscardi, Montana: AP Bieri, C Darioly, M Maire, Payerne: F Ding, P Danieli A Vonnez, Wald: D Bodmer, E Hochstrasser, R Kunz, C Meier, J Rakic, U Schafroth, A Walder. Administrative staff: C Gabriel, R Gutknecht. SHIP and SHIP-TREND. The Study of Health in Pomerania. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 41 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Caché Campus program of the InterSystems GmbH. The SHIP authors are grateful to Mario Stanke for the opportunity to use his Server Cluster for the SNP imputation as well as to Holger Prokisch and Thomas Meitinger (Helmholtz Zentrum München) for the genotyping of the SHIP-TREND cohort. TRAILS. TRacking Adolescents' Individual Lives. Trails is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grants 60- 60600-98-018 and 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 457-03-018, GB-MaGW 452-04-314, and GB-MaGW 452-06- 004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013); the Sophia Foundation for Medical Research (projects 301 and 393), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), and the participating universities. We are grateful to all adolescents, their parents and teachers who participated in this research and to everyone who worked on this project and made it possible. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. WGHS. Women's Genome Health Study. The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen. YFS. Young Finns Study. The YFS has been financially supported by the Academy of Finland: grants 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9M048 and 9N035 for TeLeht), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (T.L). The technical assistance in the statistical analyses by Ville Aalto and Irina Lisinen is acknowledged. ; Peer Reviewed
This project is focused on increasing productivity of cultivated trees in Haiti in response to the over-exploitation of native forests and conversion of forested lands to agriculture demands. ; This document summarizes the 5-year results of mahogany (Swietenia) trials in Haiti. These trials are part of a larger tree improvement program that was implemented under the USAID-funded Agroforestry II (1988-1991) project and continued during the PLUS (1992-present) project. The progeny of S. mahagoni and S. macrophylla, selected for their excellent tree form, were established in 2 orchards and 4 arboreta in 1990-1991. Three seed lots of the S. macrophylla x S. mahagoni hybrid were imported from Puerto Rico and St. Croix to compare their survival and growth with selected progeny of the parent species. S. macrophylla and S. humilis provenances were imported from Costa Rica and compared for survival and growth at 2 sites in the southwestern part of the country. Survival: Site survival after 5 years, including both S. macrophylla and S. humilis, was higher at Bérault (59%) than at Labordette (38%). Statistical differences were detected between species at the 1- and 3-year stage at Labordette and at the 1-year stage at Bérault. At both sites, S. humilis showed a higher survival rate than S. macrophylla. This superiority was still evident after 5 years, though not statistically significant at the 0.05 probability level. The S. macrophylla x S. mahagoni hybrid exhibited higher survival than either parent species at the Roche Blanche and Marmont seed orchards, but ranked the lowest of the 3 at the Marmont arboretum. Comparing the two parent species, S. mahagoni survived better than S. macrophylla at four of five trials (Fauché, Marmont arboretum, Paillant, and Roche Blanche). At the 3-year stage, survival of the hybrid averaged 57%, ranging from 51%-67%. Corresponding means for S. mahagoni was 62%, ranging from 38%-82%. S. macrophylla averaged 42%, ranging from 24%-58%. The sites tested were located within the natural range of S. mahagoni in Haiti. Differences in survival among families or seed lot varied greatly depending on site. Survival of the S. mahagoni families ranged from 0%-91% after 3 years; survival of the S. macrophylla families ranged from 0%-100%; survival of the hybrid sed lots ranged from 27%-100%. Differences in survival could not be analyzed at the family or seed lot level because the orchards and arboreta were not designed to test such differences. Height Growth: No differences were shown in height growth between S. humilis and S. macrophylla after 5 years at Bérault and Labordette. The only difference occurred at Labordette after the first year of growth with S. macrophylla 2469 showing a slight superiority over S. humilis 2470. The lowland moist site (Bérault) exhibited a mean height growth of 7.1 m after 5 years compared to 4.4 m at the mountainous site (Labordette). Differences in soil depth and moisture balances largely account for the faster growth rates observed at Bérault. The hybrid achieved mean annual growth rates of 1.0 m/yr and 1.2 m/yr at Roche Blanche and Marmont, respectively, during the first 3 years. The hybrid showed no statistical difference from the families of either parent species at the Roche Blanche orchard. The hybrid was inferior in height growth to selected families of both S. macrophylla (486) and S. mahagoni (465) at the Marmont arboretum after 1 year, but not at 3 and 5 years. At the Marmont seed orchard, the only family that showed superior height growth to the hybrid was S. macrophylla 487 at 1 year. Subsequent years showed no statistical differences among the families of the parent species and the hybrid. Significant differences in height growth between S. macrophylla and S. mahagoni was exhibited at Fauché, the wettest site, throughout the trial period of 5 years. S. macrophylla averaged 10.6 m compared to a mean height of 5.7 m of S. mahagoni. No difference in mean height growth between the two S. mahagoni families was detected. The other trials, established on much drier sites, showed no difference between the 2 species. However, differences were detected between certain families of each species at Marmont and Paillant. S. macrophylla 486 exhibited the best height growth of any single-tree family at Marmont, significantly better than 5 other S. macrophylla families (482, 483, 487, 489, and 497) and one S. mahagoni family (466) after 3 years of growth. Mean height growth of the S. macrophylla progeny ranged between 2.1 m and 6.0 m - a difference of 186% - compared to a smaller range of 3.7 m to 4.2 m - a difference of 14% - for S. mahagoni at the Marmont arboretum after 5 years. S. macrophylla 497 showed better growth than S. macrophylla 494 at Paillant after 3 years - significant at the 0.05 probability level. Diameter Growth: Differences were shown among S. humilis and S. macrophylla provenances at Bérault, but not between the 2 species. S. humilis 2470 exhibited the highest mean dbh (11.6 cm) after 5 years, which was statistically different from S. macrophylla 2469 (9.0 cm), but not the other 2 provenances. This difference was also shown for basal diameter (15.5 cm versus 13.0 cm). The exact opposite trend occurred at Labordette. S. macrophylla 2469 exhibited significantly greater stem growth than S. humilis 2470 after 5 years for both dbh and basal diameter. After 5 years, the Bérault trial averaged nearly twice the dbh growth as the trees at Labordette (10.5 cm versus 5.6 cm). The mean annual dbh rate of the hybrid after 3 years was 1.0 cm, 1.1 cm and 1.3 cm at Roche Blanche, Marmont orchard and Marmont arburetum, respectively. Stem diameter growth was stagnant during the 4th and 5th years because of severe droughts and grass competition of the trial that occurred during 1994-95. Differences in dbh and basal diamter were not shown to be significant among the hybrid, S. mahagoni and S. macrophylla species. The trials that exhibited the best growth (Fauché and the Marmont arboretum) were also the only trials that showed statistical differences among the S. mahagoni and S. macrophylla families. The mean dbh of S. macrophylla at Fauché was 11.4 cm after 5 years, equivalent to a mean annual growth rate of 2.3 cm. This was significantly better than the mean dbh of S. mahagoni (7.0 cm). At the Marmont arboretum, S. macrophylla 486 was the top-ranked mahogany family after 5 years with a mean dbh of 7.1 cm. Significant differences were exhibited between this family and the rest of the Swietenia genotypes at the 0.05 probability level. S. macrophylla 489 was the top-ranked mahogany family in the orchard during the same time period with a mean dbh of 6.8 cm. No differences were shown among the families in the orchard after 5 years at the 0.05 probability level. Merchantable Volume: The Bérault site produced 3 times the volume of lumber quality wood as Labordette. The site average per tree, including both S. humilis and S. macrophylla species, was approximately 5.77 x 10[superscript]-2 m[superscript]3 at Bérault and 1.73 x 10[superscript]-2 m[superscript]3 at Labordette. At Bérault, there was an insignificant difference between S. humilis (5.7 x 10[superscript]-2 m[superscript]3 per tree) and S. macrophylla (5.6 x 10[superscript]-2 m[superscript]3 per tree). The highest yielding provenance was S. macrophylla 1982 (6.8 x 10[superscript]-2 m[superscript]3 per tree) and the poorest production was exhibited by S. macrophylla 2469 (4.3 x 10[superscript]-2 m[superscript]3 per tree). Differences among provenances were not shown to be significant at either site. The provenances that achieved the best height and diameter growth were also the ones that exhibited the highest merchantable volume. S. macrophylla produced 3 times the volume of lumber quality wood as S. mahagoni at Fauché, on a per tree basis. However this difference decreased to double the volume, on a per hectare basis, because of the lower survival of S. macrophylla. Differences in volume yield between the 2 families of S. mahagoni were not significant at the 0.05 probability level. Recommendations: Although USAID support for this tree improvement phase of the PLUS project has ended, much needs to be done to protect Haiti's rich heritage of mahogany, and to restore the population of this valuable lumber source by making seed of selected genotypes available to farmers and land owners. The following activities are recommended to avoid jeopardizing the progress that has been accomplished to date. (1) Selectively thin the two seed orchards at Roche Blanche and Marmont by eliminating the inferior individuals and maintaining a balanced number of well-formed individuals of each genotype. The outcrossing of progeny from plus trees and the production of vigorous offspring is the first step in the production of improved seed. Seed production is not forecasted until 12-13 years of age (Lamb, 1966) or 2002. (2) Distribute seed lots from the orchards according to life zone considerations and through centralized nurseries that can track source-identified germplasm. Seed should be collected from the S. mahagoni and S. macrophylla x S. mahagoni hybrids for dry and moist forest regions of Haiti; that of S. macrophylla and the hybrids for moist to wet forest zones. Efforts should be made to study the flowering patterns of the orchard trees and observe the variability of their progeny in the nursery. Mahagony is largely pollinated by insects and normally outbreeds, but can set a high quantities of seed by self-pollination (Yang, 1965, Styles and Khosla, 1976). The orchards should be rogued based on the field performance of their progeny. (3) Selectively thin the arboreta and the S. humilis/S. macrophylla provenance trials to encourage development of the best-formed individuals. These trees should be selected based on desirable characteristics such as (1) stem form and volume, (2) pest and disease resistance, (3) symmetrical crowns and ideal crown:dbh ratio, and (4) overall survival and vigor. The S. humilis provenances are the only representatives of the species in Haiti and should be observed carefully vis-à-vis the S. macrophylla. The S. macrophylla provenances may be an important addition to the genetic diversity of the species in Haiti since most of what has spread in Haiti originates from the narrow genetic base of the stands at Franklin and Bayeux. (4) If additional orchards are established, select a wide base of plus trees, including second generation individuals located in the arboreta and orchards, and vegetatively propogate them via procedures outlined in Howard et al. (1988) and Leakey et al. (1990). Vegetative propagation of a selected genotype reduces the risk of introducing less desirable gene complexes that result from outbreeding of the mother trees. (5) Progeny trials, designed to optimally test for genetic differences among families, should be installed and monitored for a rotation age (at least 20 years) with a wide selection of genotypes from the orchards to prove their superiority over unselected genotypes. This step is critical to fulfill the requirements of certified seed. Characteristics qualifying genetic stock for the level certified must be carefully spelled out, as are the environmental conditions under which a particular genotype is expected to give above-average performance. These trials can later be rogued and converted to seed orchards for improved lines of mahogany in Haiti. They should be established with the support of the Service des Ressources Forestières, satisfying long term security and supervision requirements. (6) Monitor any natural regeneration or seedlings originating from the orchards to confirm the pattern and degree of heterosis (i.e., hybridization) and its effects on survival, growth rates and form. Most mahogany currently cultivated by Haitian farmers are pure S. mahagoni. However, demand for the hybrid may increase because of its superior form and faster growth rates on selected sites. Gene banks of pure S. mahagoni, selected throughout Haiti and the island of Hispaniola, should be established to continue efforts to conserve the remaining gene pool of a species that has economic importance, but that has been seriously high-graded throughout the history of Haiti. (7) Inform the Service des Ressources Forestière (MARNDR) of the importance and urgency to develop a long-term strategy, integrating genetic conservation and improvement of S. mahagoni as a native species of economic value. Coordinate the transfer of information from the wide range of international organizations involved with genetic conservation and improvement of mahagony in Central America and the Caribbean, particularly efforts undertaken by CATIE and IITF in collaboration with universities and international organizations (Glogiewicz, 1986; Newton et al., 1993). The government should encourage private sector investment in the certified production of mahogany wood products and seed with a view of developing management guidelines that combine conservation with production. ; Ce document résume les résultats de 5 ans de recherches sur l'acajou (Swietenia) en Haiti. Ces essais font partie d'un programme plus large d'amélioration génétique forestière qui a été implanté sous l'égide du Projet d'Agroforesterie II (1988-1991) financé par l'USAID et qui s'est poursuivi sous le Projet PLUS (de 1992 à nos jours). Les progénitures de S. mahogani et S. macrophylla, sélectionnées pour l'excellente forme de l'arbre, ont été établies dans 2 vergers et 4 arboreta en 1990-1991. Trois lots de semence de l'hybride S. macrophylla x S. mahogani ont été importés de Porto-Rico et de Ste Crois pour comparer leur survie et leur croissance à celles des progénitures sélectionnées des espèces parentales. Les provenances de S. macrophylla et S. humilis ont été importées de Costa Rica et comparées pour la survie et la croissance sur 2 sites dans le sud-ouest du pays. Survie: Après 5 ans d'établissement des essais, le taux de survie pour le site, tant pour le S. macrophylla que pour le S. humilis, a été plus élevé à Bérault (59%) qu'à Labordette (38%). Des différences statistiques ont été détectées entre les espèces à 1 et 3 ans à Labordette et à 1 an à Bérault. Aux deux sites, le S. humilis a montré un taux de survie plus élevé que le S. macrophylla. Cette supériorité a toujours persisté après 5 ans, bien qu'aucune différence statistique à 0,05 de probabilité n'ait été observée. L'hybride du S. macrophylla x S. mahogani a accusé un taux de survie plus élevé, comparé aux espèces parentales tant à Roche Blanche que dans les vergers producteur de graines de Marmont, mais s'est classé le dernier des 3 à l'arboretum de Marmont. En comparant les deux espèces parentales, le S. mahogani a mieux survécu que le S. macrophylla dans quatre des cinq essais (Fauché, arboretum de Marmont, Paillant et Roche Blanche). Au stade de 3 ans, l'hybride a accusé une survie moyenne de 57%, variant de 51% à 67%. La moyenne correspondante pour S. mahogani a été de 62%, passant de 38% à 82%. S. macrophylla a donné une moyenne de 42%, allant de 24% à 58%. Les site testés sont situés dans l'aire de distribution naturelle de S. mahogani en Haiti. Les différences de survie entre les familles ou lots de semences ont beaucoup varié dépendant du site. La survie des familles de S. mahogani a varié de 0% à 91% pendant 3 ans; celle de S. macrophylla de 0% à 100%; celle de l'hybride de 27% à 100%. Des différences de survie n'ont pas pu être analysées au niveau de la famille ou de lot de semences parce que les vergers et arboreta n'ont pas été conçus pour tester de telles différences. Croissance en Hauteur: Il n'y a eu aucune différence significative dans la croissance en hauteur entre le S. humilis et le S. macrophylla après 5 ans à Bérault et à Labordette. La seule différence s'est manifestée à Labordette après la première année de croissance avec le S. macrophylla 2469 qui a montré une légère supériorité sur le S. humilis 2470. Le site humide de basse altitude (Bérault) a accusé une croissance moyenne en hauteur de 7,1 m après 5 ans, comparé à 4,4 m au site montagneux (Labordette). Les différences de profondeur de sol et d'humidité expliquent largement les taux de croissance plus rapides observés à Bérault. L'hybride a accusé des taux de croissance annuelle de 1,0 m/an et 1,2 m/an à Roche Blanche et Marmont, respectivement, pendant les trois premières années. Il n'a pas montré de différence statistique avec les familles des espèce parentales au verger de Roche Blanche. Il s'est montré inférieur pour la croissance en hauteur comparé aux familles tant du S. macrophylla (486) que du S. mahogani (465) à l'arboretum de Marmont après 1 an, mais pas à 3 et 5 ans. Au verger à graines de Marmont, la seule famille qui ait montré une croissance en hauteur supérieure à celle de l'hybride, a été le S. macrophylla (487) à 1 an. Pour les années suivantes, il n'y a pas eu de différence significative entre les familles des espèces parentales et l'hybride. Des différences significatives de croissance en hauteur entre le S. macrophylla et le S. mahogani, ont été observées à Fauché, le site le plus humide, pour toute la période de 5 ans des essais. S. macrophylla a accusé une hauteur moyenne de 10,6 m, contre 5,7 m du S. mahogani. Aucune différence dans la croissance en hauteur entre les deux familles de S. mahogani n'a été détectée. Les autres essais, établis sur les sites plus secs, n'ont révélé aucune différence entre les 2 espèces. Cependant, des différences ont été détectées entre certaines familles de chaque espèce à Marmont et à Paillant. S. macrophylla 486 a manifesté la meilleure croissance en hauteur de famille issue d'un seul arbre à Marmont, significativement meilleure que 5 autres familles de S. macrophylla (482, 483, 487, 489, et 497) et une famille de S. mahogani (466) après 3 ans de croissance. La croissance moyenne en hauteur de la progéniture de S. macrophylla a varié entre 2,1 m et 6,0 m - une différence de 186% - comparée à une variation moins grande de 3,7 m à 4,2 m - une différence de 14% - pour le S. mahogani à l'arboretum de Marmont après 5 ans. Le S. macrophylla 497 a montré une meilleure croissance que le S. macrophylla 494 à Paillant après 3 ans - difference significative à 0,05 de probabilité. Croissance en Diamètre: Des différences ont été décelées entre les provenances de S. hummilis et de S. macrophylla à Bérault, mais pas entre les 2 espèces. S. humilis 2470 a accusé le dhp moyen le plus élevé (11,6 cm) après 5 ans, ce qui est statistiquement différent du S. macrophylla 2469 (9,0 cm), mais pas des 2 autres provenances. Cette différence à été aussi observée pour le diamètre basal (15,5 cm versus 13,0 cm). Exactement la tendance contraire a été observée à Labordette. S. macrophylla 2469 a accusé une croissance de tige significativement supérieure à celle de S. humilis 2470 après 5 ans, tant pour le dhp que pour le diamètre basal. Après 5 ans, l'essai de Bérault a donné une moyenne de croissance en dhp environ deux fois supérieure à celle des arbres à Labordette (10,5 cm versus 5,6 cm). Le taux de croissance moyenne en dhp de l'hybride après 3 ans a été de 1,0 cm, 1,1 cm et 1,3 cm au verger de Roche Blanche, à celui de Marmont et à l'arboretum de Marmont, respectivement. La croissance en diamètre de tige a été stagnante pendant les 4ème et 5ème années à cause de sécheresses sévères et de la compétition des mauvaises herbes dans l'essai pendant la période 1994-95. Les différences en dhp et diamètre basal n'ont pas été significatives entre l'hybride et les espèces de S. mahogani et S. macrophylla. Les essais qui ont montré la meilleure croissance (à Fauché et à l'arboretum de Marmont) ont été les seuls essais qui ont accusé des différences statistiques entre les familles de S. mahogani et de S. macrophylla. Le dhp moyen de S. macrophylla à Fauché a été de 11,4 cm après 5 ans, équivalent à un taux de croissance moyenne annuelle de 2,3 cm. Ce résultat a été significativement meilleur que le dhp moyen de S. mahogani (7,0 cm). A l'arboretum de Marmont, le S. macrophylla 486 a été classé le premier parmi les familles d'acajou après 5 ans, avec un dhp moyen de 7,1 cm. Des différences significatives ont été décelées entre cette famille et le reste des génotypes de Swietenia à 0,05 de probabilité. Le S. macrophylla 489 a été classé comme la meilleure famille d'acajou du verger pendant la même période avec un dhp moyen de 6,8 cm. Il n'y a pas eu de différences significatives entre les familles du verger après 5 ans à 0,05 de probabilité. Volume marchand: Le site de Bérault produisit 3 fois plus de volume de bois scié de qualité que celui de Labordette. La moyenne du site par arbre, y compris les deux espèces S. humilis et S. macrophylla, a été approximativement de 5,77 x 10[superscript]-2 m[superscript]3 à Labordette. A Bérault, il n'y a pas eu de différence significative entre le S. humilis (5,7 x 10[superscript]-2 m[superscript]3 par arbre) et le S. macrophylla (5,6 x 10[superscript]-2 m[superscript]3 par arbre). La provenance la plus productive a été le S. macrophylla 1982 (6,8 x 10[superscript]-2 m[superscript]3 par arbre) et la moins performante a été le S. macrophylla 2469 (4,3 x 10[superscript]-2 m[superscript]3 par arbre). Il n'y a pas eu de différences significatives entre les provenances à aucun des sites. Les provenances qui ont atteint la meilleure croissance en hauteur et en diamètre ont été aussi celles qui ont donné le volume de bois marchand le plus élevé. S. macrophylla produisit 3 fois plus de volume de bois scié de qualité que le S. mahogani à Fauché, sur une base par arbre. Cependant, cette différence diminua au double du volume, sur une base par hectare, à cause du plus bas taux de survie du S. macrophylla. Les différences de rendements en volume entre les 2 familles du S. mahogani n'ont pas été significatives à 0,05 de probabilité. Recommandations: Bien que le financement par l'USAID de la section d'amélioration génétique forestière ait pris fin, il reste encore beaucoup à faire pour protéger le riche héritage de l'acajou, et pour restaurer la population de cette source de bois précieux en mettant à la disposition des fermiers et des propriétaires terriens, des semences de génotypes sélectionnés. Les activités suivantes sont recommandées pour éviter de perdre les bénéfices de ce qui a été accompli jusqu'ici: (1) Procéder à l'éclairie sélective des deux vergers à Roche Blanche et Marmont, en éliminant les individus inférieurs et en maintenant une quantité équilibrée d'individus bien formés de chaque génotype. Le croisement entre progénitures des arbres sélectionnés et la production de descendants vigoureux est la première étape dans la production de semences améliorées. La production de semences n'est pas prévue avant l'âge de 12-13 ans (Lamb, 1996) ou avant 2002. (2) Distribuer des lots de semences provenant des vergers en tenant compte des zones écologiques et à travers des pépinières centralisées qui permettent de suivre la trace du germoplasme de sources identifiées. Des semences de S. mahogani et des hybrides de S. macrophylla x S. mahogani devraient être collectées pour les régions forestières humides d'Haiti; celles du S. macrophylla et des hybrides pour les zones forestières humides et pluvieuses. Des efforts devraient être faits pour étudier les époques de floraison des arbres des vergers et observer la variabilité de leurs progénitures en pépinière. L'acajou est largement pollinisé par les insectes et par la pollinisation croisée naturelle, mais peut donner une grande quantité de semences par auto-pollinisation (Yang, 1965; Styles et Khosla, 1976). Les vergers devraient être sélectionnés sur la base de la performance des progénitures sur le terrain. (3) Procéder à des éclaircies sélectives des arboreta et des essais de provenances de S. humilis et de S. macrophylla pour encourager le développement des individus les mieux formés. Ces arbres devraient être sélectionnés sur las base de caractéristiques désirables telles que: (1) forme de tige et volume, (2) résistance aux pestes et aux maladies, (3) couronnes symétriques et rapport couronne idéale:dhp, et (4) survie générale et vigeur. Les provenances de S. humilis sont les seuls représentants de l'espèce en Haiti et devraient être observées soigneusement par rapport au S. macrophylla. Les provenances de S. macrophylla peuvent constituer un important apport à la diversité génétique de l'espèce en Haiti, étant donné que ce qui a été promu en Haiti vient de la base génétique étroite des peuplements établis à Franklin et Bayeux. (4) Si de nouveaux vergers sont établis, sélectionner une large base d'arbres phénotypiquement supérieurs, y compris la seconde génération d'individus dans les arboreta et les vergers, et les propager végétativement via des procédures esquissées dans Howard et al. (1988) et Leakey et al. (1990). La propagation végétative de génotypes sélectionnés réduit les risques d'introduire des complexes de gènes moins désirables résultant du croisement des arbres-mères. (5) Des essais de progénitures, planifiés pour tester de façon optimum les différences génétiques entre les familles, devraient être installés et suivis pour une période de rotation (au moins 20 ans) avec une sélection large de génotypes venant des vergers pour prouver leur supériorité sur les génotypes non sélectionnés. Cette étape est critique pour satisfaire les exigences de semences certifiées. Les critères de qualification du stock génétique pour las certification devraient être clairement définis, aussi bien que les conditions environnementales sous lesquelles un génotype particulier est supposé donner une performance au-dessus de la moyenne. Ces essais peuvent être éliminés plus tard et convertis en vergers producteurs de graines pour des lignées améliorées d'acajou en Haiti. Ils devraient être établis avec le support du Service des Ressources Forestières, pour répondre aux exigences de sécurité à long terme et de supervision. (6) Contrôler toute régénération naturelle ou plantules venant des vergers pour confirmer le modèle et le degré d'hétérosis (i.e. hybridation) et ses effets sur la survie, les taux de croissance et la forme. La plupart des acajous plantés en Haiti sont des lignées pures de S. mahagoni. Cependant, la demande pour l'hybride peut augmenter à cause de la supériorité de sa forme et les taux de croissance plus rapides sur les sites testés. Les banques de gènes de lignées pures de S. mahogani, sélectionnées à travers Haiti et l'île d'Hispaniola, devraient être établies pour continuer les efforts de conserver le mélange génétique restant d'une espèce économiquement importante, qui a toujours été considérée comme une espèce de bois précieux en Haiti. (7) Informe le Service des Ressources Forestières du MARNDR de l'importance et de l'urgence de développer une stratégie à long terme, intégrant la conservation génétique et l'amélioration du S. mahogani comme une espèce indigène de valeur économique. Coordonner le transfert des informations venant d'une série d'organisations internationales impliquées dans la conservation génétique et l'amélioration de l'acajou en Amérique Centrale et dans les Caraibes. Citons particulièrement les efforts entrepris par CATIE et IITF dans la collaboration avec des universités et des organisations internationales (Glogiewicz, 1986, Newton et al., 1993). Le gouvernement devrait encourager le secteur privé à investir dans la production de produit fabriqués avec du bois d'acajou certifé et de semences avec pour objectif de développer des grandes lignes de gestion qui combinent la conservation et la production.
Publisher's version (útgefin grein) ; Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors. ; Peterlongo laboratory is supported by Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo and by a fellowship from Fondazione Umberto Veronesi to G. Figlioli. Surrallés laboratory is supported by the ICREA-Academia program, the Spanish Ministry of Health (projects FANCOSTEM and FANCOLEN), the Spanish Ministry of Economy and Competiveness (projects CB06/07/0023 and RTI2018-098419-B-I00), the European Commission (EUROFANCOLEN project HEALTH-F5-2012-305421 and P-SPHERE COFUND project), the Fanconi Anemia Research Fund Inc, and the "Fondo Europeo de Desarrollo Regional, una manera de hacer Europa" (FEDER). CIBERER is an initiative of the Instituto de Salud Carlos III, Spain. BCAC: we thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. ABCFS thank Maggie Angelakos, Judi Maskiell, Tu Nguyen-Dumont is a National Breast Cancer Foundation (Australia) Career Development Fellow. ABCS thanks the Blood bank Sanquin, The Netherlands. Samples are made available to researchers on a non-exclusive basis. BCEES thanks Allyson Thomson, Christobel Saunders, Terry Slevin, BreastScreen Western Australia, Elizabeth Wylie, Rachel Lloyd. The BCINIS study would not have been possible without the contributions of Dr. Hedy Rennert, Dr. K. Landsman, Dr. N. Gronich, Dr. A. Flugelman, Dr. W. Saliba, Dr. E. Liani, Dr. I. Cohen, Dr. S. Kalet, Dr. V. Friedman, Dr. O. Barnet of the NICCC in Haifa, and all the contributing family medicine, surgery, pathology and oncology teams in all medical institutes in Northern Israel. The BREOGAN study would not have been possible without the contributions of the following: Manuela Gago-Dominguez, Jose Esteban Castelao, Angel Carracedo, Victor Muñoz Garzón, Alejandro Novo Domínguez, Maria Elena Martinez, Sara Miranda Ponte, Carmen Redondo Marey, Maite Peña Fernández, Manuel Enguix Castelo, Maria Torres, Manuel Calaza (BREOGAN), José Antúnez, Máximo Fraga and the staff of the Department of Pathology and Biobank of the University Hospital Complex of Santiago-CHUS, Instituto de Investigación Sanitaria de Santiago, IDIS, Xerencia de Xestion Integrada de Santiago-SERGAS; Joaquín González-Carreró and the staff of the Department of Pathology and Biobank of University Hospital Complex of Vigo, Instituto de Investigacion Biomedica Galicia Sur, SERGAS, Vigo, Spain. BSUCH thanks Peter Bugert, Medical Faculty Mannheim. CBCS thanks study participants, co-investigators, collaborators and staff of the Canadian Breast Cancer Study, and project coordinators Agnes Lai and Celine Morissette. CCGP thanks Styliani Apostolaki, Anna Margiolaki, Georgios Nintos, Maria Perraki, Georgia Saloustrou, Georgia Sevastaki, Konstantinos Pompodakis. CGPS thanks staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgård Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases. Investigators from the CPS-II cohort thank the participants and Study Management Group for their invaluable contributions to this research. They also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, as well as cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. The CTS Steering Committee includes Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, and Eunjung Lee at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, Hoda Anton-Culver, Argyrios Ziogas, and Hannah Park at the University of California Irvine, and Fred Schumacher at Case Western University. DIETCOMPLYF thanks the patients, nurses and clinical staff involved in the study. The DietCompLyf study was funded by the charity Against Breast Cancer (Registered Charity Number 1121258) and the NCRN. We thank the participants and the investigators of EPIC (European Prospective Investigation into Cancer and Nutrition). ESTHER thanks Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach. FHRISK thanks NIHR for funding. GC-HBOC thanks Stefanie Engert, Heide Hellebrand, Sandra Kröber and LIFE - Leipzig Research Centre for Civilization Diseases (Markus Loeffler, Joachim Thiery, Matthias Nüchter, Ronny Baber). The GENICA Network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany [HB, Wing-Yee Lo], German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) [HB], Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2180 - 390900677 [HB], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [Ute Hamann], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]. HABCS thanks Michael Bremer. HEBCS thanks Heidi Toiminen, Kristiina Aittomäki, Irja Erkkilä and Outi Malkavaara. HMBCS thanks Peter Hillemanns, Hans Christiansen and Johann H. Karstens. HUBCS thanks Shamil Gantsev. KARMA thanks the Swedish Medical Research Counsel. KBCP thanks Eija Myöhänen, Helena Kemiläinen. LMBC thanks Gilian Peuteman, Thomas Van Brussel, EvyVanderheyden and Kathleen Corthouts. MABCS thanks Milena Jakimovska (RCGEB "Georgi D. Efremov), Katerina Kubelka, Mitko Karadjozov (Adzibadem-Sistina" Hospital), Andrej Arsovski and Liljana Stojanovska (Re-Medika" Hospital) for their contributions and commitment to this study. MARIE thanks Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels. MBCSG (Milan Breast Cancer Study Group) thanks Daniela Zaffaroni, Irene Feroce, and the personnel of the Cogentech Cancer Genetic Test Laboratory. We thank the coordinators, the research staff and especially the MMHS participants for their continued collaboration on research studies in breast cancer. MSKCC thanks Marina Corines and Lauren Jacobs. MTLGEBCS would like to thank Martine Tranchant (CHU de Québec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital; McGill University) for DNA extraction, sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. NBHS thanks study participants and research staff for their contributions and commitment to the studies. We would like to thank the participants and staff of the Nurses' Health Study and Nurses' Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. The authors assume full responsibility for analyses and interpretation of these data. OFBCR thanks Teresa Selander and Nayana Weerasooriya. ORIGO thanks E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao and Michael Stagner. The ethical approval for the POSH study is MREC /00/6/69, UKCRN ID: 1137. We thank staff in the Experimental Cancer Medicine Centre (ECMC) supported Faculty of Medicine Tissue Bank and the Faculty of Medicine DNA Banking resource. PREFACE thanks Sonja Oeser and Silke Landrith. PROCAS thanks NIHR for funding. RBCS thanks Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Anja Kromwijk-Nieuwlaat, Annette Heemskerk, the Erasmus MC Family Cancer Clinic. We thank the SEARCH and EPIC teams. SKKDKFZS thanks all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. We thank the SUCCESS Study teams in Munich, Duessldorf, Erlangen and Ulm. SZBCS thanks Ewa Putresza. UCIBCS thanks Irene Masunaka. UKBGS thanks Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. CIMBA: we are grateful to all the families and clinicians who contribute to the studies; Sue Healey, in particular taking on the task of mutation classification with the late Olga Sinilnikova; Maggie Angelakos, Judi Maskiell, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Griškevičius; Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management; Bent Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants; Alicia Barroso, Rosario Alonso and Guillermo Pita; all the individuals and the researchers who took part in CONSIT TEAM (Consorzio Italiano Tumori Ereditari Alla Mammella), thanks in particular: Giulia Cagnoli, Roberta Villa, Irene Feroce, Mariarosaria Calvello, Riccardo Dolcetti, Giuseppe Giannini, Laura Papi, Gabriele Lorenzo Capone, Liliana Varesco, Viviana Gismondi, Maria Grazia Tibiletti, Daniela Furlan, Antonella Savarese, Aline Martayan, Stefania Tommasi, Brunella Pilato, Isabella Marchi, Elena Bandieri, Antonio Russo, Daniele Calistri and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. FPGMX: members of the Cancer Genetics group (IDIS): Ana Blanco, Miguel Aguado, Uxía Esperón and Belinda Rodríguez. We thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study and the collaborating groups in Lahore, Pakistan (Noor Muhammad, Sidra Gull, Seerat Bajwa, Faiz Ali Khan, Humaira Naeemi, Saima Faisal, Asif Loya, Mohammed Aasim Yusuf) and Bogota, Colombia (Diana Torres, Ignacio Briceno, Fabian Gil). Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014. The team in Lyon (Olga Sinilnikova, Mélanie Léoné, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Valérie Sornin) managed the GEMO samples until the biological resource centre was transferred to Paris in December 2015 (Noura Mebirouk, Fabienne Lesueur, Dominique Stoppa-Lyonnet). We want to thank all the GEMO collaborating groups for their contribution to this study. Drs.Sofia Khan, Irja Erkkilä and Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, M.K. Schmidt, N.S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C.M. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam Medical Center, NL: C.M. Aalfs, H.E.J. Meijers-Heijboer; VU University Medical Center, Amsterdam, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez-Garcia, M.J. Blok; University of Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J.Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): A.W. van den Belt-Dusebout. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. Overbeek; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Zoltan Matrai, Miklos Kasler, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study; HVH (University Hospital Vall d'Hebron) the authors acknowledge the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d'Hebron, Miguel Servet Progam (CP10/00617), and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Catarina Santos and Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab investigators, research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Kevin Sweet, Caroline Craven, Julia Cooper, Amber Aielts, and Michelle O'Conor; Christina Selkirk; Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad and Salina Chan; Carole Pye, Patricia Harrington and Eva Wozniak. OSUCCG thanks Kevin Sweet, Caroline Craven, Julia Cooper, Michelle O'Conor and Amber Aeilts. BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union's Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l'Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, and the Quebec Breast Cancer Foundation. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The Australian Breast Cancer Tissue Bank (ABCTB) was supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The AHS study is supported by the intramural research program of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia. For the BCFR-NY, BCFR-PA, BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BCINIS study was funded by the BCRF (The Breast Cancer Research Foundation, USA). The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). Sample collection and processing was funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the Canadian Institutes of Health Research. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, K05 CA136967, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK is funded from NIHR grant PGfAR 0707-10031. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler, Cologne). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf Bartling Foundation. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HMBCS was supported by a grant from the German Research Foundation (Do 761/10-1). The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), and by the Russian Foundation for Basic Research and the Federal Agency for Scientific Organizations for support the Bioresource collections and RFBR grants 14-04-97088, 17-29-06014 and 17-44-020498. E.K was supported by the program for support the bioresource collections №007-030164/2 and study was performed as part of the assignment of the Ministry of Science and Higher Education of Russian Federation (№АААА-А16-116020350032-1). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. LMBC is supported by the 'Stichting tegen Kanker'. DL is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov" and supported by the German Academic Exchange Program, DAAD. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 × 1000"). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839 and CA164973. The MISS study is supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286 and CA177150. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) were supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The Carolina Breast Cancer Study was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, U01 CA179715), and the North Carolina University Cancer Research Fund. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107, and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956 and Breast Cancer Campaign 2010PR62, 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation and the Swedish Research Council [grant 2017-00644 for the Swedish Infrastructure for Medical Population-based Life-course Environmental Research (SIMPLER)]. The SZBCS is financially supported under the program of Minister of Science and Higher Education "Regional Initiative of Excellence" in years 2019-2022, Grant No 002/RID/2018/19. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. CIMBA CIMBA: The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research -UK Senior Cancer Research Fellow. GCT and ABS are NHMRC Research Fellows. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015 and Nr. P-MIP-19-164. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant number R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT TEAM: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547) to P. Radice. Funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 × 1000') to S. Manoukian. UNIROMA1: Italian Association for Cancer Research (AIRC; grant no. 21389) to L. Ottini. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: NIH/NCI grant P30-CA006927. The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. Ana Vega is supported by the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII), partially supported by FEDER funds through Research Activity Intensification Program (contract grant numbers: INT15/00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018); Autonomous Government of Galicia (Consolidation and structuring program: IN607B), and by the Fundación Mutua Madrileña (call 2018). GC-HBOC: German Cancer Aid (grant no 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program, the French National Institute of Cancer (INCa) (grants AOR 01 082, 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015) and the Fondation ARC pour la recherche sur le cancer (grant PJA 20151203365). GEORGETOWN: the Survey, Recruitment and Biospecimen Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008) and the Fisher Center for Hereditary Cancer and Clinical Genomics Research. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI_OTKA K-112228. HVH (University Hospital Vall d'Hebron) This work was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds: FIS PI12/02585 and PI15/00355. ICO: The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and "Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa" (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563, P18/01029, and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, 2017SGR449, and PERIS Project MedPerCan), and CERCA program. IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and "5 × 1000" Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NCI: the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. NNPIO: the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-45012). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: was funded by the Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance and the Breast Cancer research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Researc h UK. UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. ; Peer Reviewed
Publisher's version (útgefin grein). ; Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis. ; The authors in this manuscript were working on behalf of BCAC, CCFR, CIMBA, CORECT, GECCO, OCAC, PRACTICAL, CRUK, BPC3, CAPS, PEGASUS, TRICL-ILCCO, ABCTB, APCB, BCFR, CONSIT TEAM, EMBRACE, GC-HBOC, GEMO, HEBON, kConFab/AOCS Mod SQuaD, and SWE-BRCA. The breast cancer genome-wide association analyses: BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union's Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST, respectively), and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l'Économie, Science et Innovation du Québec through Genome Québec and the PSR-SIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The DRIVE Consortium was funded by U19 CA148065. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The Australian Breast Cancer Tissue Bank (ABCTB) is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The ACP study is funded by the Breast Cancer Research Trust, UK. The AHS study is supported by the intramural research program of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia and acknowledges funding from the National Breast Cancer Foundation (JS). For the BCFR-NY, BCFR-PA, and BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. For BIGGS, ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. BOCS is supported by funds from Cancer Research UK (C8620/A8372/A15106) and the Institute of Cancer Research (UK). BOCS acknowledges NHS funding to the Royal Marsden/Institute of Cancer Research NIHR Specialist Cancer Biomedical Research Centre. The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CAMA study was funded by Consejo Nacional de Ciencia y Tecnología (CONACyT) (SALUD-2002-C01-7462). Sample collection and processing was funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the Canadian Institutes of Health Research. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI12/00070). COLBCCC is supported by the German Cancer Research Center (DKFZ), Heidelberg, Germany. D.T. was in part supported by a postdoctoral fellowship from the Alexander von Humboldt Foundation. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. H.A.C eceives support from the Lon V Smith Foundation (LVS39420). The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK is funded from NIHR grant PGfAR 0707-10031. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler, Cologne). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, and 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). GLACIER was supported by Breast Cancer Now, CRUK and Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London. The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf-Bartling Foundation. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HERPACC was supported by MEXT Kakenhi (No. 170150181 and 26253041) from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, by National Cancer Center Research and Development Fund, and "Practical Research for Innovative Cancer Control (15ck0106177h0001)" from Japan Agency for Medical Research and development, AMED, and Cancer Bio Bank Aichi. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), and by the Russian Foundation for Basic Research and the Federal Agency for Scientific Organizations for support the Bioresource collections and RFBR grants 14-04-97088, 17-29-06014, and 17-44-020498. ICICLE was supported by Breast Cancer Now, CRUK, and Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (A.L.F.) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (E.V.O.) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.-T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. The KOHBRA study was partially supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. L.M.B.C. is supported by the 'Stichting tegen Kanker'. D.L. is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov" and supported by the German Academic Exchange Program, DAAD. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 × 1000"). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839, and CA164973. The MISS study is supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286, and CA177150. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Malaysia. MYMAMMO is supported by research grants from Yayasan Sime Darby LPGA Tournament and Malaysian Ministry of Higher Education (RP046B-15HTM). The NBCS has been supported by the Research Council of Norway grant 193387/V50 (to A.-L. Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A.-L. Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A.-L. Børresen-Dale and 27208 to V.N. Kristensen) and the Norwegian Cancer Society (to A.-L. Børresen-Dale and 419616 - 71248 - PR-2006-0282 to V.N. Kristensen). It has received funding from the K.G. Jebsen Centre for Breast Cancer Research (2012-2015). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) were supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The Carolina Breast Cancer Study was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, and U01 CA179715), and the North Carolina University Cancer Research Fund. The NGOBCS was supported by Grants-in-Aid for the Third Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan, and for Scientific Research on Priority Areas, 17015049 and for Scientific Research on Innovative Areas, 221S0001, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107, and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation, and the special Governmental EVO funds for Oulu University Hospital-based research activities. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956, and Breast Cancer Campaign 2010PR62, 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, UMCA182910, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now Tissue Bank. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute, Thailand. The TNBCC was supported by a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centers, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The WAABCS study was supported by grants from the National Cancer Institute of the National Institutes of Health (R01 CA89085 and P50 CA125183 and the D43 TW009112 grant), Susan G. Komen (SAC110026), the Dr. Ralph and Marian Falk Medical Research Trust, and the Avon Foundation for Women. The WHI program is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C). This work was also funded by NCI U19 CA148065-01. D.G.E. is supported by the all Manchester NIHR Biomedical research center Manchester (IS-BRC-1215-20007). HUNBOCS, Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grant KTIA-OTKA CK-80745, NKFI_OTKA K-112228. C.I. received support from the Nontherapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI P30-CA-51008) and the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research. K.M. is supported by CRUK C18281/A19169. City of Hope Clinical Cancer Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J Weitzel) from the National Cancer Institute and the office of the Directory, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The colorectal cancer genome-wide association analyses: Colorectal Transdisciplinary Study (CORECT): The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CORECT Consortium, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the CORECT Consortium. We are incredibly grateful for the contributions of Dr. Brian Henderson and Dr. Roger Green over the course of this study and acknowledge them in memoriam. We are also grateful for support from Daniel and Maryann Fong. ColoCare: we thank the many investigators and staff who made this research possible in ColoCare Seattle and ColoCare Heidelberg. ColoCare was initiated and developed at the Fred Hutchinson Cancer Research Center by Drs. Ulrich and Grady. CCFR: the Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff, and financial support from the U.S. National Cancer Institute, without which this important registry would not exist. Galeon: GALEON wishes to thank the Department of Surgery of University Hospital of Santiago (CHUS), Sara Miranda Ponte, Carmen M Redondo, and the staff of the Department of Pathology and Biobank of CHUS, Instituto de Investigación Sanitaria de Santiago (IDIS), Instituto de Investigación Sanitaria Galicia Sur (IISGS), SERGAS, Vigo, Spain, and Programa Grupos Emergentes, Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain. MCCS: this study was made possible by the contribution of many people, including the original investigators and the diligent team who recruited participants and continue to work on follow-up. We would also like to express our gratitude to the many thousands of Melbourne residents who took part in the study and provided blood samples. SEARCH: We acknowledge the contributions of Mitul Shah, Val Rhenius, Sue Irvine, Craig Luccarini, Patricia Harrington, Don Conroy, Rebecca Mayes, and Caroline Baynes. The Swedish low-risk colorectal cancer study: we thank Berith Wejderot and the Swedish low-risk colorectal cancer study group. Genetics & Epidemiology of Colorectal Cancer Consortium (GECCO): we thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. ASTERISK: we are very grateful to Dr. Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik, and Ursula Eilber for excellent technical assistance. HPFS, NHS and PHS: we acknowledge Patrice Soule and Hardeep Ranu of the Dana-Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS, and PHS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo, and Lixue Zhu who assisted in programming for NHS and HPFS and Haiyan Zhang who assisted in programming for the PHS. We thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: A.L., A.Z., A.R., C.A., C.O., C.T., D.E., F.L., G.A., I.D., I.L., I.N., I.A., K.Y., L.A., M.E., M.D., M.A., M.I., N.E., N.H., N.J., N.Y., N.C., N.D., O.H., O.K., O.R., P.A., R.I., S.C., T.N., T.X., V.A., W.A., W.Y. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. We assume full responsibility for analyses and interpretation of these data. PLCO: we thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services Inc., Ms. Barbara O'Brien and staff, Westat Inc. and Drs. Bill Kopp, Wen Shao and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions for making this study possible. The statements contained herein are solely those of the authors and do not represent or imply concurrence or endorsement by NCI. PMH: we thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short20List.pdf. CORECT: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; and R01 CA201407) and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). The ATBC Study was supported by the US Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute. The Cancer Prevention Study-II Nutrition Cohort is funded by the American Cancer Society. ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184, U01 CA206110, 2P30CA015704-40 (Gilliland)), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): funding for GECCO was provided by the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (grant numbers U01 CA137088, R01 CA059045, and U01 CA164930). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S.G.). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number UM1 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806), Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai'i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C, and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: A.Z., C.O., M.N., N.C., N.H., and by the Victoria Cancer Registry and Ontario Cancer Registry. ESTHER/VERDI was supported by grants from the Baden–Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. GALEON: FIS Intrasalud (PI13/01136). The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MSKCC: the work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). SEARCH: Cancer Research UK (C490/A16561). The Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Catalan Government DURSI (grant 2014SGR647), and Junta de Castilla y León (grant LE22A10-2). The Swedish Low-risk Colorectal Cancer Study: the study was supported by grants from the Swedish research council; K2015-55 × -22674-01-4, K2008-55 × -20157-03-3, K2006-72 × -20157-01-2 and the Stockholm County Council (ALF project). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I (to K.D.), through grant 101HG007491-01 (to C.I.A.). The Norris Cotton Cancer Center - P30CA023108, The Quantitative Biology Research Institute - P20GM103534, and the Coordinating Center for Screen Detected Lesions - U01CA196386 also supported efforts of C.I.A. This work was also supported by the National Cancer Institute (grant numbers U01 CA1817700, R01 CA144040). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (grant number R01 CA060987). DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1, and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). DALS: National Institutes of Health (grant number R01 CA048998 to M.L.S). HPFS is supported by National Institutes of Health (grant numbers P01 CA055075, UM1 CA167552, R01 137178, and P50 CA127003), NHS by the National Institutes of Health (grant numbers UM1 CA186107, R01 CA137178, P01 CA087969, and P50 CA127003), NHSII by the National Institutes of Health (grant numbers R01 050385CA and UM1 CA176726), and PHS by the National Institutes of Health (grant number R01 CA042182). MEC: National Institutes of Health (grant numbers R37 CA054281, P01 CA033619, and R01 CA063464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (grant number U01 CA074783); see Colon CFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J.H. and B.W.Z. are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples was genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, 23 and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (grant number R01 CA076366). VITAL: National Institutes of Health (grant number K05-CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The head and neck cancer genome-wide association analyses: The study was supported by NIH/NCI: P50 CA097190, and P30 CA047904, Canadian Cancer Society Research Institute (no. 020214) and Cancer Care Ontario Research Chair to R.H. The Princess Margaret Hospital Head and Neck Cancer Translational Research Program is funded by the Wharton family, Joe's Team, Gordon Tozer, Bruce Galloway and the Elia family. Geoffrey Liu was supported by the Posluns Family Fund and the Lusi Wong Family Fund at the Princess Margaret Foundation, and the Alan B. Brown Chair in Molecular Genomics. This publication presents data from Head and Neck 5000 (H&N5000). H&N5000 was a component of independent research funded by the UK National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) in H&N5000 serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). National Cancer Institute (R01-CA90731); National Institute of Environmental Health Sciences (P30ES10126). The authors thank all the members of the GENCAPO team/The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). CPS-II recruitment and maintenance is supported with intramural research funding from the American Cancer Society. Genotyping performed at the Center for Inherited Disease Research (CIDR) was funded through the U.S. National Institute of Dental and Craniofacial Research (NIDCR) grant 1 × 01HG007780-0. The University of Pittsburgh head and neck cancer case-control study is supported by National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01-CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). The authors thank all the members of the GENCAPO team. The HN5000 study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034), the views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Toronto study was funded by the Canadian Cancer Society Research Institute (020214) and the National Cancer Institute (U19-CA148127) and the Cancer Care Ontario Research Chair. The alcohol-related cancers and genetic susceptibility study in Europe (ARCAGE) was funded by the European Commission's 5th Framework Program (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte, and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2011 10491 and IG2013 14220 to S.B., and Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97-0222), with additional funding from Fondo para la Investigacion Cientifica y Tecnologica (Argentina) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (01/01768-2). We thank Leticia Fernandez, Instituto Nacional de Oncologia y Radiobiologia, La Habana, Cuba and Sergio and Rosalina Koifman, for their efforts with the IARC Latin America study São Paulo center. The IARC Central Europe study was supported by European Commission's INCO-COPERNICUS Program (IC15- CT98-0332), NIH/National Cancer Institute grant CA92039, and the World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662, and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The lung cancer genome-wide association analyses: Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by (U19-CA148127, CA148127S1, U19CA203654, and Cancer Prevention Research Institute of Texas RR170048). The ILCCO data harmonization is supported by Cancer Care Ontario Research Chair of Population Studies to R. H. and Lunenfeld-Tanenbaum Research Institute, Sinai Health System. The TRICL-ILCCO OncoArray was supported by in-kind genotyping by the Centre for Inherited Disease Research (26820120008i-0-26800068-1). The CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989-01A1(PI Doherty). The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, CA074386. The Multi-ethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464, and CA148127. The work performed in MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study (SCS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The Singapore Chinese Health Study (SCHS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997), and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The Vanderbilt Lung Cancer Study—BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center's BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH. Dr. Aldrich was supported by NIH/National Cancer Institute K07CA172294 (PI: Aldrich) and Dr. Bush was supported by NHGRI/NIH U01HG004798 (PI: Crawford). The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number: 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The M.D. Anderson Cancer Center study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568) (to X.W.), Cancer Prevention & Research Institute of Texas (RP130502) (to X.W.), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The deCODE study of smoking and nicotine dependence was funded in part by a grant from NIDA (R01- DA017932). The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer—field study. Genetic sharing analysis was funded by NIH grant CA194393. The research undertaken by M.D.T., L.V.W., and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The work to assemble the FTND GWAS meta-analysis was supported by the National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA) grant number R01 DA035825 (Principal Investigator [PI]: DBH). The study populations included COGEND (dbGaP phs000092.v1.p1 and phs000404.v1.p1), COPDGene (dbGaP phs000179.v3.p2), deCODE Genetics, EAGLE (dbGaP phs000093.vs.p2), and SAGE. dbGaP phs000092.v1.p1). See Hancock et al. Transl Psychiatry 2015 (PMCID: PMC4930126) for the full listing of funding sources and other acknowledgments. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT)study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. The ovarian cancer genome-wide association analysis: The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium that was funded by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The OCAC OncoArray genotyping project was funded through grants from the U.S. National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.), and R01-CA058598 (M.T.G.); Canadian Institutes of Health Research (MOP-86727 (L.E.K.) and the Ovarian Cancer Research Fund (A.B.). The COGS project was funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175) and through a grant from the U.S. National Institutes of Health (R01-CA122443 (E.L.G)). Funding for individual studies: AAS: National Institutes of Health (RO1-CA142081); AOV: The Canadian Institutes for Health Research (MOP-86727); AUS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600, 400413 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia (Multi-State Applications 191, 211, and 182). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation; BAV: ELAN Funds of the University of Erlangen-Nuremberg; BEL: National Kankerplan; BGS: Breast Cancer Now, Institute of Cancer Research; BVU: Vanderbilt CTSA grant from the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) (ULTR000445); CAM: National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre; CHA: Innovative Research Team in University (PCSIRT) in China (IRT1076); CNI: Instituto de Salud Carlos III (PI12/01319); Ministerio de Economía y Competitividad (SAF2012); COE: Department of Defense (W81XWH-11-2-0131); CON: National Institutes of Health (R01-CA063678, R01-CA074850; and R01-CA080742); DKE: Ovarian Cancer Research Fund; DOV: National Institutes of Health R01-CA112523 and R01-CA87538; EMC: Dutch Cancer Society (EMC 2014-6699); EPC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom); GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ); GRC: This research has been co-financed by the European Union (European Social Fund—ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF)—Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund; GRR: Roswell Park Cancer Institute Alliance Foundation, P30 CA016056; HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424, and N01-PC-67001); HJO: Intramural funding; Rudolf-Bartling Foundation; HMO: Intramural funding; Rudolf-Bartling Foundation; HOC: Helsinki University Research Fund; HOP: Department of Defense (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, P50-CA159981 MO1-RR000056 R01-CA126841); HUO: Intramural funding; Rudolf-Bartling Foundation; JGO: JSPS KAKENHI grant; JPN: Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare; KRA: This study (Ko-EVE) was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 0920010); LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; LUN: ERC-2011-AdG 294576-risk factors cancer, Swedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation; MAC: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Fraternal Order of Eagles; MAL: Funding for this study was provided by research grant R01- CA61107 from the National Cancer Institute, Bethesda, MD, research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project; MAS: Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, and P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: Cancer Council Victoria, National Health and Medical Research Council of Australia (NHMRC) grants number 209057, 251533, 396414, and 504715; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); MEC: NIH (CA54281, CA164973, CA63464); MOF: Moffitt Cancer Center, Merck Pharmaceuticals, the state of Florida, Hillsborough County, and the city of Tampa; NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: UM1 CA186107, P01 CA87969, R01 CA49449, R01-CA67262, UM1 CA176726; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720) and the Cancer Institute of New Jersey; If Sara Olson and/or Irene Orlow is a co-author, please add NCI CCSG award (P30-CA008748) to the funding sources; NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; OPL: National Health and Medical Research Council (NHMRC) of Australia (APP1025142) and Brisbane Women's Club; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; PLC: Intramural Research Program of the National Cancer Institute; POC: Pomeranian Medical University; POL: Intramural Research Program of the National Cancer Institute; PVD: Canadian Cancer Society and Cancer Research Society GRePEC Program; RBH: National Health and Medical Research Council of Australia; RMH: Cancer Research UK, Royal Marsden Hospital; RPC: National Institute of Health (P50-CA159981, R01-CA126841); SEA: Cancer Research UK (C490/A10119 C490/A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; SIS: NIH, National Institute of Environmental Health Sciences, Z01-ES044005 and Z01-ES049033; SMC: The bbSwedish Research Council-SIMPLER infrastructure; the Swedish Cancer Foundation; SON: National Health Research and Development Program, Health Canada, grant 6613-1415-53; SRO: Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589); STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and VårKampMotCancer foundation; SWH: NIH (NCI) grant R37-CA070867; TBO: National Institutes of Health (R01-CA106414-A2), American Cancer Society (CRTG-00-196-01-CCE), Department of Defense (DAMD17-98-1-8659), Celma Mastery Ovarian Cancer Foundation; TOR: NIH grants R01-CA063678 and R01 CA063682; UCI: NIH R01-CA058860 and the Lon V Smith Foundation grant LVS39420; UHN: Princess Margaret Cancer Centre Foundation-Bridge for the Cure; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre; UKR: Cancer Research UK (C490/A6187), UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; USC: P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200); VAN: BC Cancer Foundation, VGH & UBC Hospital Foundation; VTL: NIH K05-CA154337; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 & 15/RIG/1-16; WOC: National Science Centren (N N301 5645 40). The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academia Reserve. The prostate cancer genome-wide association analyses: we pay tribute to Brian Henderson, who was a driving force behind the OncoArray project, for his vision and leadership, and who sadly passed away before seeing its fruition. We also thank the individuals who participated in these studies enabling this work. The ELLIPSE/PRACTICAL (http//:practical.icr.ac.uk) prostate cancer consortium and his collaborating partners were supported by multiple funding mechanisms enabling this current work. ELLIPSE/PRACTICAL Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA148537 for ELucidating Loci Involved in Prostate Cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I). Additional analytical support was provided by NIH NCI U01 CA188392 (F.R.S.). Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112; the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This work was supported by the Canadian Institutes of Health Research, European Commission's Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, C5047/A21332 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA148537-01 (the GAME-ON initiative). We also thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, and The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The Prostate Cancer Program of Cancer Council Victoria also acknowledge grant support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, and 614296), VicHealth, Cancer Council Victoria, The Prostate Cancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers, and Tattersall's. E.A.O., D.M.K., and E.M.K. acknowledge the Intramural Program of the National Human Genome Research Institute for their support. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). CAPS GWAS study was supported by the Swedish Cancer Foundation (grant no 09-0677, 11-484, 12-823), the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (grant no K2010-70 × -20430-04-3, 2014-2269). The Hannover Prostate Cancer Study was supported by the Lower Saxonian Cancer Society. PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. RAPPER was supported by the NIHR Manchester Biomedical Research Center, Cancer Research UK (C147/A25254, C1094/A18504) and the EU's 7th Framework Programme Grant/Agreement no 60186. Overall: this research has been conducted using the UK Biobank Resource (application number 16549). NHS is supported by UM1 CA186107 (NHS cohort infrastructure grant), P01 CA87969, and R01 CA49449. NHSII is supported by UM1 CA176726 (NHSII cohort infrastructure grant), and R01-CA67262. A.L.K. is supported by R01 MH107649. We would like to thank the participants and staff of the NHS and NHSII for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. ; Peer Reviewed