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Publisher's version (útgefin grein) ; Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p[BI]= 4.4 × 10-10; p [SSBI] = 1.2 × 10 -4), diabetes (p[BI] = 1.7 × 10 -8; p [SSBI] = 2.8 × 10 -3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI. ; CHAP: R01-AG-11101, R01-AG-030146, NIRP-14-302587. SMART: This study was supported by a grant from the Netherlands Organization for Scientific Research–Medical Sciences (project no. 904-65–095). LBC: The authors thank the LBC1936 participants and the members of the LBC1936 research team who collected and collated the phenotypic and genotypic data. The LBC1936 is supported by Age UK (Disconnected Mind Programme grant). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). The brain imaging was performed in the Brain Research Imaging Centre (https://www.ed.ac.uk/clinical-sciences/edinburgh-imaging), a center in the SINAPSE Collaboration (sinapse.ac.uk) supported by the Scottish Funding Council and Chief Scientist Office. Funding from the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the UK Medical Research Council is acknowledged. Genotyping was supported by a grant from the BBSRC (ref. BB/F019394/1). PROSPER: The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SCES and SiMES: National Medical Research Council Singapore Centre Grant NMRC/CG/013/2013. C.-Y.C. is supported by the National Medical Research Council, Singapore (CSA/033/2012), Singapore Translational Research Award (STaR) 2013. Dr. Kamran Ikram received additional funding from the Singapore Ministry of Health's National Medical Research Council (NMRC/CSA/038/2013). SHIP: 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 "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 Healthineers, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. Whole-body MRI was supported by a joint grant from Siemens Healthineers, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. OATS (Older Australian Twins Study): OATS was supported by an Australian National Health and Medical Research Council (NHRMC)/Australian Research Council (ARC) Strategic Award (ID401162) and by a NHMRC grant (ID1045325). OATS was facilitated via access to the Australian Twin Registry, which is supported by the NHMRC Enabling Grant 310667. The OATS genotyping was partly supported by a Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant. NOMAS: The Northern Manhattan Study is funded by the NIH grant "Stroke Incidence and Risk Factors in a Tri-Ethnic Region" (NINDS R01NS 29993). TASCOG: NHMRC and Heart Foundation. AGES: The study was funded by the National Institute on Aging (NIA) (N01-AG-12100), Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament), with contributions from the Intramural Research Programs at the NIA, the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Neurological Disorders and Stroke (NINDS) (Z01 HL004607-08 CE). ERF: The ERF study as a part of European Special Populations Research Network (EUROSPAN) was supported by European Commission FP6 STRP grant no. 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007–2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). Exome sequencing analysis in ERF was supported by the ZonMw grant (project 91111025). Najaf Amin is supported by the Netherlands Brain Foundation (project no. F2013[1]-28). ARIC: The Atherosclerosis Risk in Communities study was performed as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant no. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This project was also supported by NIH R01 grant NS087541 to M.F. FHS: This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contracts no. N01-HC-25195 and no. HHSN268201500001I), 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. This study was also supported by grants from the NIA (R01s AG033040, AG033193, AG054076, AG049607, AG008122, and U01-AG049505) and the NINDS (R01-NS017950, UH2 NS100605). Dr. DeCarli is supported by the Alzheimer's Disease Center (P30 AG 010129). ASPS: The research reported in this article was funded by the Austrian Science Fund (FWF) grant nos. P20545-P05, P13180, and P20545-B05, by the Austrian National Bank Anniversary Fund, P15435, and the Austrian Ministry of Science under the aegis of the EU Joint Programme–Neurodegenerative Disease Research (JPND) (jpnd.eu). LLS: The Leiden Longevity Study has received funding from the European Union's Seventh Framework Programme (FP7/2007–2011) under grant agreement no. 259679. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (grant 050-060-810), all in the framework of the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO), UnileverColworth, and by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007). CHS: This CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC15103, and HHSN268200960009C and grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL085251, and R01HL130114 from the NHLBI with additional contribution from NINDS. Additional support was provided through R01AG023629 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Rotterdam Study: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research (NWO) Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/NWO project no. 050-060-810. The Rotterdam Study is funded by Erasmus MC Medical Center and Erasmus MC University, Rotterdam, Netherlands Organization for 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. M.A.I. is supported by an NWO Veni grant (916.13.054). The 3-City Study: The 3-City Study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Bordeaux, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l'Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Programme "Cohortes et collections de données biologiques." C.T. and S.D. have received investigator-initiated research funding from the French National Research Agency (ANR) and from the Fondation Leducq. S.D. is supported by a starting grant from the European Research Council (SEGWAY), a grant from the Joint Programme of Neurodegenerative Disease research (BRIDGET), from the European Union's Horizon 2020 research and innovation programme under grant agreements No 643417 & No 640643, and by the Initiative of Excellence of Bordeaux University. Part of the computations were performed at the Bordeaux Bioinformatics Center (CBiB), University of Bordeaux. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille, the Labex DISTALZ, and the Centre National de Génotypage. ADGC: The Alzheimer Disease Genetics Consortium is supported by NIH. NIH-NIA supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Banner Sun Health Research Institute, P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant NS39764, NIMH MH60451, and by GlaxoSmithKline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232, the Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council [MRC], local NHS trusts, and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England [HEFCE], Alzheimer's Research Trust [ART], BRACE, as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, and Universitat de Barcelona). ADNI: Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, and K01 AG030514. Support was also provided by the Alzheimer's Association (LAF, IIRG-08-89720; MAP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. SiGN: Stroke Genetic Network (SiGN) was supported in part by award nos. U01NS069208 and R01NS100178 from NINDS. Genetics of Early-Onset Stroke (GEOS) Study was supported by the NIH Genes, Environment and Health Initiative (GEI) grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488); and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to Johns Hopkins University (contract no. HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S. Weir). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention, and by grants from NINDS and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). METASTROKE: ASGC: Australian population control data were derived from the Hunter Community Study. This research was funded by grants from the Australian National and Medical Health Research Council (NHMRC Project Grant ID: 569257), the Australian National Heart Foundation (NHF Project Grant ID: G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme, and the Vincent Fairfax Family Foundation in Australia. E.G.H. was supported by a Fellowship from the NHF and National Stroke Foundation of Australia (ID: 100071). J.M. was supported by an Australian Postgraduate Award. BRAINS: Bio-Repository of DNA in Stroke (BRAINS) is partly funded by a Senior Fellowship from the Department of Health (UK) to P.S., the Henry Smith Charity, and the UK-India Education Research Institutive (UKIERI) from the British Council. GEOS: Genetics of Early Onset Stroke (GEOS) Study, Baltimore, was supported by GEI Grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488), and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract no. HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S. Weir). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention, and by grants from NINDS and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). HPS: Heart Protection Study (HPS) (ISRCTN48489393) was supported by the UK MRC, British Heart Foundation, Merck and Co. (manufacturers of simvastatin), and Roche Vitamins Ltd. (manufacturers of vitamins). Genotyping was supported by a grant to Oxford University and CNG from Merck and Co. J.C.H. acknowledges support from the British Heart Foundation (FS/14/55/30806). ISGS: Ischemic Stroke Genetics Study (ISGS)/Siblings With Ischemic Stroke Study (SWISS) was supported in part by the Intramural Research Program of the NIA, NIH project Z01 AG-000954-06. ISGS/SWISS used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (ccr.coriell.org/ninds), human subjects protocol nos. 2003-081 and 2004-147. ISGS/SWISS used stroke-free participants from the Baltimore Longitudinal Study of Aging (BLSA) as controls. The inclusion of BLSA samples was supported in part by the Intramural Research Program of the NIA, NIH project Z01 AG-000015-50, human subjects protocol no. 2003-078. The ISGS study was funded by NIH-NINDS Grant R01 NS-42733 (J.F.M.). The SWISS study was funded by NIH-NINDS Grant R01 NS-39987 (J.F.M.). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (biowulf.nih.gov). MGH-GASROS: MGH Genes Affecting Stroke Risk and Outcome Study (MGH-GASROS) was supported by NINDS (U01 NS069208), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research 0775010N, the NIH and NHLBI's STAMPEED genomics research program (R01 HL087676), and a grant from the National Center for Research Resources. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research resources. Milan: Milano–Besta Stroke Register Collection and genotyping of the Milan cases within CEDIR were supported by the Italian Ministry of Health (grant nos.: RC 2007/LR6, RC 2008/LR6; RC 2009/LR8; RC 2010/LR8; GR-2011-02347041), FP6 LSHM-CT-2007-037273 for the PROCARDIS control samples. WTCCC2: Wellcome Trust Case-Control Consortium 2 (WTCCC2) was principally funded by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). The Stroke Association provided additional support for collection of some of the St George's, London cases. The Oxford cases were collected as part of the Oxford Vascular Study, which is funded by the MRC, Stroke Association, Dunhill Medical Trust, National Institute of Health Research (NIHR), and the NIHR Biomedical Research Centre, Oxford. The Edinburgh Stroke Study was supported by the Wellcome Trust (clinician scientist award to C.L.M.S.) and the Binks Trust. Sample processing occurred in the Genetics Core Laboratory of the Wellcome Trust Clinical Research Facility, Western General Hospital, Edinburgh. Much of the neuroimaging occurred in the Scottish Funding Council Brain Imaging Research Centre (https://www.ed.ac.uk/clinical-sciences/edinburgh-imaging), Division of Clinical Neurosciences, University of Edinburgh, a core area of the Wellcome Trust Clinical Research Facility, and part of the SINAPSE (Scottish Imaging Network: A Platform for Scientific Excellence) collaboration (sinapse.ac.uk), funded by the Scottish Funding Council and the Chief Scientist Office. Collection of the Munich cases and data analysis was supported by the Vascular Dementia Research Foundation. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreements no. 666881, SVDs@target (to M.D.) and no. 667375, CoSTREAM (to M.D.); the DFG as part of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy) and the CRC 1123 (B3) (to M.D.); the Corona Foundation (to M.D.); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain) (to M.D.); the e:Med program (e:AtheroSysMed) (to M.D.) and the FP7/2007-2103 European Union project CVgenes@target (grant agreement no. Health-F2-2013-601456) (to M.D.). M.F. and A.H. acknowledge support from the BHF Centre of Research Excellence in Oxford and the Wellcome Trust core award (090532/Z/09/Z). VISP: The GWAS component of the Vitamin Intervention for Stroke Prevention (VISP) study was supported by the US National Human Genome Research Institute (NHGRI), grant U01 HG005160 (PI Michèle Sale and Bradford Worrall), as part of the Genomics and Randomized Trials Network (GARNET). Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to Johns Hopkins University. Assistance with data cleaning was provided by the GARNET Coordinating Center (U01 HG005157; PI Bruce S. Weir). Study recruitment and collection of datasets for the VISP clinical trial were supported by an investigator-initiated research grant (R01 NS34447; PI James Toole) from the US Public Health Service, NINDS, Bethesda, MD. Control data obtained through the database of genotypes and phenotypes (dbGAP) maintained and supported by the United States National Center for Biotechnology Information, US National Library of Medicine. WHI: Funding support for WHI-GARNET was provided through the NHGRI GARNET (grant no. U01 HG005152). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GARNET Coordinating Center (U01 HG005157). Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the GEI (U01 HG004424). R.L. is a senior clinical investigator of FWO Flanders. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001–Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre. ; Peer Reviewed

Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified ARas mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. in its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIAWorld Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children. (J Allergy Clin Immunol 2012;130:1049-62.) ; Stallergenes ; ALK-Abello ; European Academy of Allergy and Clinical Immunology (EAACI) ; MSD ; Novartis ; Nycomed/Takeda ; PHADIA/Thermo Fischer ; 3M ; AstraZeneca ; GlaxoSmithKline ; Merck Frosst ; Altair ; Amgen ; Asmacure ; Boehringer-Ingelheim ; Genentech ; Pharmaxis ; Schering ; Wyeth ; Ache ; Brazilian Research Council ; Fundacao de Amparo a Pesquisa da Bahia ; Fundacao Ciencia e Tecnologia ; Sociedade Portuguesa de Alergologia e Immunologia Clinica ; Abdi Ibrahim ; OrionPharma ; Nasonebs ; Merck ; McNeal ; Chiesi ; Nycomed ; Air Liquid Healthcare ; Mundipharma ; Almirall ; Kyorin ; Teva ; UK National Health Service ; Aerocrine ; AKL Ltd ; PREDICTA ; Swiss National Science Foundation ; MeDALL ; Global Allergy and Asthma European Network (GA 2LEN) ; Christine Kuthe Center for Allergy Research and Education ; Faes Farma ; Bial ; Johnson Johnson ; Sanofi ; HAD treasurer ; Innovative Medicine Initiative (EU) ; Helse Sor-Ost RHF (Southern and Eastern Norway Regional Health Authority) ; MEDA ; Alcon ; ISTA ; Thermo-Fisher ; Airsonett ; Medical Research Council ; Moulton Charitable Trust ; AB Science ; Canadian Institutes for Health Research ; AllerGen NCE ; Merck/Schering-Plough ; Circassia ; University Hospital ; Medical School of Universidad Autonoma de Nuevo Leon, Mexico ; Children's Research Foundation (Ireland) ; Danone ; Food Standards Agency (United Kingdom) ; European Union (EU) ; DTG ; Netherlands Asthma Foundation ; Merck-Sharp-Dohme, Mexico ; Allerquim Mexico ; Abbott ; Apotex ; HRA ; MedImmune ; Schering-Plough ; Proctor Gamble ; Sunovion (Sepracor) ; Phadia ; Servier ; CSC JohnsonJohnson ; Oxygen Plus ; New Medics ; European Respiratory Society ; Societe de Pneumologie de Langue Francaise Asthma ; Ministry of Health, Welfare, and Labor ; Altana ; Takeda ; UCB ; Uriach advisory board ; NAPP ; Royal College of GPs Clinical Champion in Allergy ; Agency for Healthcare Research and Quality (AHRQ) ; AnseII ; Bayer Schering ; OST ; Fujisawa ; IHAL ; Henkel ; Kryolan ; Leti ; MSO ; Procter and Gamble ; Sanofi-Aventis ; Scientific Advisory Board for the German Society for Allergy and Clinical Immunology ; German Federal Ministry of Consumer Protection ; European Centre for Allergy Research Foundation (ECARF) ; Hop Arnaud Villeneuve, Dept Resp Dis, Univ Hosp, Montpellier, France ; INSERM, U1018, CESP Ctr Res Epidemiol & Populat Hlth, Resp & Environm Epidemiol Team, Villejuif, France ; McMaster Univ, Dept Clin Epidemiol & Biostat & Med, Hamilton, ON, Canada ; Med Univ Warsaw, Dept Prevent Environm Hazards & Allergol, Warsaw, Poland ; Univ Hosp Montpellier, Hop Arnaud Villeneuve, INSERM, U657, Montpellier, France ; Catholic Univ, Fac Med, Res Ctr Resp Med CIMER, Cordoba, Argentina ; Univ Genoa, Sch Specializat, Genoa, Italy ; Univ Ghent, Dept Otorhinolaryngol, Upper Airways Res Lab, B-9000 Ghent, Belgium ; CNR, Inst Translat Pharmacol, Rome, Italy ; Univ Naples 2, Naples, Italy ; Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada ; Univ Genoa, Dept Internal Med, DIMI, I-16126 Genoa, Italy ; Creighton Univ, Dept Med, Div Allergy & Immunol, Omaha, NE 68178 USA ; Univ Fed Bahia, ProAR Nucleo Excelencia Asma, Salvador, BA, Brazil ; CNPq, Salvador, BA, Brazil ; Univ Amsterdam, Dept Otorhinolaryngol, NL-1012 WX Amsterdam, Netherlands ; Univ Amsterdam, Acad Med Ctr, Dept Otorhinolaryngol, NL-1105 AZ Amsterdam, Netherlands ; Univ Porto, Sch Med, Dept Hlth Informat & Decis Sci, P-4100 Oporto, Portugal ; Univ Porto, Sch Med, CINTESIS, P-4100 Oporto, Portugal ; Hosp S Joao & Inst, Dept Allergy, Oporto, Portugal ; Hosp CUF Porto, Oporto, Portugal ; Erasmus MC, Dept Internal Med, Sect Allergol, Rotterdam, Netherlands ; Univ Washington, Sch Med, Seattle, WA USA ; Helsinki Univ Hosp, Dept Allergy, Skin & Allergy Hosp, Helsinki, Finland ; GARD ARIA Coordinator, Geneva, Switzerland ; Med Univ Lodz, Dept Internal Med Asthma & Allergy, Barlicki Univ Hosp, Lodz, Poland ; Univ S Florida, Coll Med, Dept Internal Med, Div Allergy & Immunol, Tampa, FL 33612 USA ; James A Haley Vet Hosp, Tampa, FL USA ; Univ Oslo, Oslo Univ Hosp, Dept Paediat, Oslo, Norway ; CIBERES, IDIBAPS, Hosp Clin, Rhinol Unit,ENT Dept, Barcelona, Spain ; CIBERES, IDIBAPS, Hosp Clin, Smell Clin,ENT Dept, Barcelona, Spain ; Univ Chicago, Dept Otolaryngol Head & Neck Surg, Chicago, IL 60637 USA ; Alfred Hosp, Dept Allergy Immunol & Resp Med, Melbourne, Vic, Australia ; Monash Univ, Melbourne, Vic 3004, Australia ; Teikyo Univ, Sch Med, Dept Med, Div Resp Med & Allergol, Tokyo 173, Japan ; EFA European Federat Allergy & Airways Dis Patien, Brussels, Belgium ; Univ Athens, Dept Allergy, Pediat Clin 2, Athens, Greece ; Nippon Med Sch, Bunkyo Ku, Tokyo 113, Japan ; Univ Aberdeen, Dept Primary Care Resp Med, Aberdeen, Scotland ; Woodbrook Med Ctr, Loughborough, Leics, England ; Univ Edinburgh, Edinburgh, Midlothian, Scotland ; Univ Manitoba, Fac Med, Winnipeg, MB, Canada ; NIAID, Bethesda, MD 20892 USA ; Univ N Carolina, Sch Pharm, Chapel Hill, NC USA ; Celal Bayar Univ, Sch Med, Dept Pulmonol, Manisa, Turkey ; Allergy & Asthma Inst, Islamabad, Pakistan ; Med Univ Graz, Dept Dermatol, Graz, Austria ; Showa Univ, Sch Med, Div Allergol & Resp Med, Tokyo 142, Japan ; Transylvania Univ, Fac Med, Brasov, Romania ; Int Union TB & Lung Dis Union, Paris, France ; Univ Zurich, Swiss Inst Allergy & Asthma Res SIAF, Davos, Switzerland ; Minist Hlth, Publ Hosp Med Serv, Antananarivo, Madagascar ; INSERM, EPAR U707, Paris, France ; Univ Paris 06, EPAR, UMR S, Paris, France ; Hosp Quiron Bizkaia, Dept Allergy & Immunol, Erandio Bilbao, Spain ; Univ Cape Town, Dept Med, Fac Hlth Sci, Div Pulmonol, ZA-7925 Cape Town, South Africa ; WHO, Collaborating Ctr Asthma & Rhinitis, Montpellier, France ; Univ Modena & Reggio Emilia, Dept Oncol Hematol & Resp Dis, Modena, Italy ; Ctr Hosp Univ Rabta, Serv Pneumol Allergol, Tunis, Tunisia ; Univ Amsterdam, Acad Med Ctr, Dept Pulmonol, NL-1105 AZ Amsterdam, Netherlands ; Hop Mami, Ariana, Tunisia ; Bangladesh Lung Fdn, Dhaka, Bangladesh ; Natl Inst Dis Chest & Hosp, Dhaka, Bangladesh ; Charite, Dept Dermatol, Allergy Ctr Charite, D-13353 Berlin, Germany ; Univ Med Ctr, Dept Dermatol & Allergy, Bonn, Germany ; Odense Univ Hosp, Dept Dermatol, DK-5000 Odense, Denmark ; Odense Univ Hosp, Allergy Ctr, DK-5000 Odense, Denmark ; Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA ; Univ Verona, Dept Paediat, I-37100 Verona, Italy ; Univ Laval, Fac Med, Quebec City, PQ G1K 7P4, Canada ; Hop Malbaie, La Malbaie, PQ, Canada ; Univ Leicester, Inst Lung Hlth, Leicester LE1 7RH, Leics, England ; Royal Brompton Hosp, Dept Paediat Resp Med, London SW3 6LY, England ; Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Sect Allergy & Clin Immunol, London, England ; Ctr Med Docente La Trinidad Caracas, Dept Immunol, Caracas, Venezuela ; Univ Austral Chile, Fac Med, Dept Pediat, Valdivia, Chile ; Univ Fed Sao Joao del Rei, Hlth Sci Ctr, Hlth Sci Postgrad Program, Divinopolis, Brazil ; Univ Cartagena, Immunol Res Inst, Cartagena de Indias, Colombia ; So Calif Res, Mission Viejo, CA USA ; Metropolitan Univ Barranquilla, Allergy & Immunol Lab, Barranquilla, Colombia ; IRCCS San Raffaele Pisana, Rome, Italy ; Univ Cattolica Sacro Cuore, Dept Thorac Surg, Rome, Italy ; Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands ; Capital Inst Pediat, Asthma Clin, Natl Cooperat Grp Pediat Res Asthma, Beijing, Peoples R China ; Capital Inst Pediat, Educ Ctr, Beijing, Peoples R China ; Ctr Asthma Res & Educ, Beijing, Peoples R China ; Hop Arnaud Villeneuve, Univ Hosp, Allergy Unit, Montpellier, France ; Univ Hosp, Dept Allergol, Sch Med CEU San Pablo Madrid, Madrid, Spain ; Georgian Natl Univ, AIETI Med Sch, SEU Clin, Med Ctr, Tbilisi, Rep of Georgia ; Univ Genoa, Dept Internal Med, IRCCS Azienda Osped Univ San Martino, I-16126 Genoa, Italy ; Univ Montpellier I, Primary Care Dept, Montpellier, France ; Nova SE Univ, Coll Osteopath Med, Davie, FL USA ; Univ Manchester, Manchester, Lancs, England ; Aarhus Univ Hosp, Dept Resp Dis, DK-8000 Aarhus, Denmark ; Tech Univ Munich, Dept Dermatol & Allergy Biederstein, Munich, Germany ; TUM, Div Environm Dermatol, Munich, Germany ; TUM, Allergy Helmholtz Ctr, Munich, Germany ; Univ Hosp Strasbourg, Chest Dis Dept, Div Pulmonol Asthma & Allergol, Strasbourg, France ; Univ Med & Pharm Iuliu Hatieganu, Dept Allergy, Med Clin 3, Romanian Soc Allergy & Clin Immunol, Cluj Napoca, Romania ; McMaster Univ, AllerGen NCE, Dept Med, Hamilton, ON, Canada ; McMaster Univ, AllerGen NCE, Michael G DeGroote Sch Med, Div Clin Immunol & Allergy,Fac Hlth Sci, Hamilton, ON, Canada ; Univ Versailles St Quentin, Hop Foch, UPRES EA 220, Suresnes, France ; Ctr Hosp Reg Annecy, Serv Pneumol, Annecy, France ; Univ Ss Cyril & Methodius, Univ Clin Pulmonol & Allergy, Skopje, Macedonia ; Georgia Hlth Sci Univ, Augusta, GA USA ; Ctr Hosp Univ Beni Messous, Serv Pneumoallergol, Algiers, Algeria ; Vilnius Univ, Fac Med, Collaborating Ctr GA2LEN, Vilnius, Lithuania ; Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England ; Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA ; Ain Shams Univ, Childrens Hosp, Pediat Allergy & Immunol Unit, Cairo, Egypt ; Egyptian Soc Pediat Allergy & Immunol, Cairo, Egypt ; Soc Marocaine Malad Resp, Casablanca, Morocco ; Ctr Resp Dis & Allergy, Casablanca, Morocco ; Vilnius Univ, Fac Med, Vilnius, Lithuania ; Univ Milan, Sch Med, Melloni Hosp, Milan, Italy ; Educ Hlth, Warwick, England ; Dokkyo Med Univ, Mibu, Tochigi, Japan ; WHO, Country Off Georgia, Tbilisi, Rep of Georgia ; Clin Ricardo Palma, Lima, Peru ; Univ Nuevo Leon UANL, Hosp Univ, Fac Med, Monterrey, Mexico ; Ctr Allergy & Immunol, Tbilisi, Rep of Georgia ; Clin Hosp Univ Chile, Dept Med, Immunol & Allergol Div, Santiago, Chile ; Univ Hosp Leuven, Dept Otorhinolaryngol Head & Neck Surg, Louvain, Belgium ; Cent Reg Denmark, Ctr Publ Hlth & Qual Improvement, Aarhus, Denmark ; Allergy Ctr Vienna W, Vienna, Austria ; Natl Univ Ireland Univ Coll Cork, Dept Paediat & Child Hlth, Cork, Ireland ; Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England ; Univ Paris 11, Serv Pneumol, Hop Antoine Beclere, AP HP,INSERM,U999, Clamart, France ; Salvador Univ, Sch Med, Dept Immunol, Buenos Aires, DF, Argentina ; Univ St Andrews, St Andrews, Fife, Scotland ; Univ Paris, APHP, Ctr Asthme & Allergies, Grp Hosp Trousseau La Roche Guyon, F-75252 Paris, France ; Hacettepe Univ, Sch Med, Pediat Allergy & Asthma Unit, Ankara, Turkey ; George Washington Univ, Sch Med, Washington, DC USA ; Inst Asthma & Allergy, Chevy Chase, MD USA ; Hacettepe Univ Hosp, Dept Chest Dis, Adult Allergy Unit, Ankara, Turkey ; Charite, Inst Social Med Epidemiol & Hlth Econ, D-13353 Berlin, Germany ; McMaster Univ, Hamilton, ON, Canada ; Hotel Dieu France, Serv Pneumol & Reanimat Med, Beirut, Lebanon ; Univ St Joseph, Fac Med, Beirut, Lebanon ; Natl Med Ctr, Seoul, South Korea ; Seoul Natl Univ, Seoul, South Korea ; Korea Asthma Allergy Fdn, Seoul, South Korea ; Ctr Hosp Univ, Serv Malad Resp, Abidjan, Cote Ivoire ; Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Beatrix Childrens Hosp,Dept Pediat Pulmonol & Ped, Groningen, Netherlands ; Med Univ Lodz, Dept Immunol Rheumatol & Allergy, Lodz, Poland ; Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden ; Karolinska Inst, Sachs Childrens Hosp, Stockholm, Sweden ; Vilnius Univ, Ctr Pulmonol & Allergol, Vilnius, Lithuania ; Vilnius Univ Hosp Santariskiu Klinikos, Vilnius, Lithuania ; Hosp Med Sur, Dept Allergy, Mexico City, DF, Mexico ; Univ Med & Pharm, Thanh Pho Ho Chi Minh, Vietnam ; Hop Sacre Coeur Montreal, Montreal, PQ, Canada ; Univ Montreal, Montreal, PQ, Canada ; Guangzhou Med Univ, Affiliated Hosp 1, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China ; Univ Tennessee, Coll Med, Memphis, TN USA ; Univ Dundee, Ninewells Hosp, Asthma & Allergy Res Grp, Dundee, Scotland ; Dubai Hlth Author, Sharjah, U Arab Emirates ; Univ Sharjah, Sharjah, U Arab Emirates ; Univ Mississippi, Med Ctr, Div Clin Immunol & Allergy, Jackson, MS 39216 USA ; Univ Arizona, Coll Med, Arizona Resp Ctr, Tucson, AZ USA ; Univ Arizona, Inst BIO5, Tucson, AZ USA ; Shahid Beheshti Univ Med Sci, NRITLD, Tehran, Iran ; Shahid Beheshti Univ Med Sci, Chron Resp Dis Res Ctr, Tehran, Iran ; Charite, Dept Dermatol & Allergy, D-13353 Berlin, Germany ; Maputo Cent Hosp, Dept Peadiat, Maputo, Mozambique ; Eduardo Mondlane Univ, Fac Med, Maputo, Mozambique ; Childrens Hosp La Fe, Unit Pediat Allergy & Pneumol, Valencia, Spain ; Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden ; Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden ; Univ Calif San Diego, Allergy & Asthma Med Grp, San Diego, CA 92103 USA ; Univ Calif San Diego, Res Ctr, San Diego, CA 92103 USA ; IMSS, Dept Allergy & Clin Immunol, Ctr Med Nacl Siglo 21, Mexico City, DF, Mexico ; Univ Aachen, Dept Dermatol, Aachen, Germany ; Inst Pneumol Marius Nasta, Bucharest, Romania ; Tishreen Univ, Sch Med, Dept Internal Med, WHO EMRO Collaborating Ctr Training & Res Chron R, Latakia, Syria ; CUF Descobertas Hosp, Immunoallergy Dept, Lisbon, Portugal ; Univ Padua, Dept Pediat, Food Allergy Referral Ctr Veneto Reg, Padua, Italy ; Mustapha Hosp, Algiers, Algeria ; Sci Ctr Childrens Hlth RAMS, Moscow, Russia ; Hosp Hospitaller Bros Buda, Budapest, Hungary ; Charite, Allergie Ctr Charite ECARF, Dept Dermatol Venerol & Allergy, D-13353 Berlin, Germany ; German Red Cross Hosp Westend, Berlin, Germany ; Jagiellonian Univ, Sch Med, Dept Pulmonol, Krakow, Poland ; Kinshasa Univ, ENT Dept, Kinshasa, Zaire ; Chiba Univ Hosp, Dept Otorhinolaryngol, Chiba, Japan ; Nippon Med Sch, Dept Otolaryngol, Bunkyo Ku, Tokyo 113, Japan ; Ctr Hosp Univ Pediat Charles de Gaulle, Ouagadougou, Burkina Faso ; Marmara Univ, Div Pediat Allergy & Immunol, Istanbul, Turkey ; Mem Hlth Grp, Istanbul, Turkey ; Charles Univ Prague, Fac Med Plzen, Dept Immunol & Allergol, Prague, Czech Republic ; MESSERLI Res Inst, Vienna, Austria ; Med Univ Vienna, Univ Vet Med Vienna, Vienna, Austria ; Univ Vienna, Vienna, Austria ; Ajou Univ, Sch Med, Suwon 441749, South Korea ; NICE, Paris, France ; Soc Pneumol Langue Francaise, Paris, France ; Krankenhaus Hietzing, Karl Landsteiner Inst Expt & Clin Pneumol, Dept Pulm Med, Vienna, Austria ; Alexanders Univ Hosp, Clin Allergy & Asthma, Sofia, Bulgaria ; Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Pulmonol, Groningen, Netherlands ; Univ Cape Town, Lung Inst, ZA-7925 Cape Town, South Africa ; Groote Schuur Hosp, ZA-7925 Cape Town, South Africa ; Leiden Univ, Dept Pulmonol, Med Ctr, Leiden, Netherlands ; Grosshansdorf Clin, Grosshansdorf, Germany ; Hop Prive Athis Mons, Serv Pneumol, Athis Mons, France ; Helsinki Univ Hosp, Dept Dermatol, Skin & Allergy Hosp, Helsinki, Finland ; Tech Univ Munich, CKCARE, Dept Dermatol Allergy Biederstein, Munich, Germany ; Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA ; Med Univ Silesia, Dept & Clin Internal Dis Allergol & Clin Immunol, Katowice, Poland ; Complesso Integrato Columbus, Allergy Unit, Rome, Italy ; IRCCS Oasi Maria SS, Troina, Italy ; Son Pisa Primary Care Ctr, IB Salut Balear Hlth Serv, Int Primary Care Resp Grp, Palma de Mallorca, Spain ; Hosp Luz, Immunoallergy Dept, Lisbon, Portugal ; Univ Missouri, Kansas City Sch Med, Kansas City, MO 64110 USA ; Childrens Mercy Hosp, Kansas City, MO USA ; Emek Med Ctr, Afula, Israel ; Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel ; Ctr Med Docente La Trinidad, Dept Allergy & Clin Immunol, Caracas, Venezuela ; UCL, Royal Natl TNE Hosp, London, England ; Univ Zurich Hosp, Dept Dermatol, Allergy Unit, CH-8091 Zurich, Switzerland ; Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Allergy & Resp Res Grp, Edinburgh, Midlothian, Scotland ; Universidade Federal de São Paulo, Dept Pediat, Div Allergy Clin Immunol & Rheumatol, São Paulo, Brazil ; Natl Ctr Cardiol & Internal Med, Bishkek, Kyrgyzstan ; Ctr ACI Immunoflow, Czech Initiat Asthma, Prague, Czech Republic ; GAAPP, Vienna, Austria ; Ctr Res Environm Epidemiol CREAL, Barcelona, Spain ; Pontificia Univ Catolica RGS, Sch Med, Porto Alegre, RS, Brazil ; Univ Nevada, Sch Med, Reno, NV 89557 USA ; Hosp Mar, Municipal Inst Med Res IMIM, Barcelona, Spain ; CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain ; Univ Pompeu Fabra UPF, Barcelona, Spain ; Jagiellonian Univ, Coll Med, Krakow, Poland ; Coimbra Univ Hosp, Immunoallergy Dept, Coimbra, Portugal ; Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA ; Finnish Inst Occupat Hlth, Helsinki, Finland ; Univ Laval, Fac Med, Dept Obstet & Gynecol, Laval, PQ, Canada ; Med Univ Vienna, Christian Doppler Lab Allergy Res, Div Immunopathol, Dept Pathophysiol & Allergy Res,Ctr Pathophysiol, Vienna, Austria ; Hosp Clin Barcelona, Dept Pneumol, Allergy Unit, Immunoallergia Resp Clin, Barcelona, Spain ; IDIBAPS, Barcelona, Spain ; CIBERES, Barcelona, Spain ; Univ Paris 13, Bobigny, France ; Avicenne Hosp, AP HP, Bobigny, France ; Vilnius Univ, Fac Med, Dept Paediat, Vilnius, Lithuania ; Lithuanian Natl Council Childs Hlth, Vilnius, Lithuania ; Terveystalo Turku, Allergy Clin, Turku, Finland ; Univ Turku, Dept Lung Dis & Clin Immunol, Turku, Finland ; Univ Ghent, Dept Otorhinolaryngol, B-9000 Ghent, Belgium ; Catholic Univ Louvain, Univ Hosp Mt Godinne, Yvoir, Belgium ; Radboud Univ Nijmegen, Med Ctr, Dept Primary & Community Care, NL-6525 ED Nijmegen, Netherlands ; Siriraj Hosp, Fac Med, Dept Pediat, Bangkok, Thailand ; CNR, IBIM, Palermo, Italy ; Clin Physiol IFC, Pisa, Italy ; Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 117595, Singapore ; Floridsdorf Allergy Ctr FAZ, Vienna, Austria ; Med Univ Vienna, Dept Dermatol, DIAID, Vienna, Austria ; Bradford Teaching Hosp Fdn Trust, Bradford Inst Hlth Res, Bradford, W Yorkshire, England ; Olmsted Med Ctr, Dept Res, Rochester, MN USA ; Univ Minnesota, Dept Family & Community Hlth, Rochester, MN USA ; Harvard Univ, Sch Publ Hlth, Cyprus Int Inst Environm & Publ Hlth Assoc, Limassol, Cyprus ; Cyprus Univ Technol, Limassol, Cyprus ; Univ Cape Town, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, ZA-7925 Cape Town, South Africa ; Catholic Univ Cordoba, Sch Med, Dept Otorhinolaryngol, Cordoba, Argentina ; Guangzhou Med Univ, Guangzhou Inst Resp Dis, Guangzhou, Guangdong, Peoples R China ; Guangzhou Med Univ, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China ; Univ Clin Resp & Allerg Dis, Golnik, Slovenia ; Charite, Network Excellence, Global Allergy & Asthma European Network GA2LEN, D-13353 Berlin, Germany ; Universidade Federal de São Paulo, Dept Pediat, Div Allergy Clin Immunol & Rheumatol, São Paulo, Brazil ; Web of Science

High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species1,2,3,4. To address this issue, the international Genome 10K (G10K) consortium5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences. ; We thank them for their permission to publish. A.R., S.K., B.P.W. and A.M.P. were supported by the Intramural Research Program of the NHGRI, NIH (1ZIAHG200398). A.R. was also supported by the Korea Health Technology R&D Project through KHIDI, funded by the Ministry of Health & Welfare, Republic of Korea (HI17C2098). S.A.M., I.B. and R.D. were supported by Wellcome Trust grant WT207492; W.C., M. Smith, Z.N., Y.S., J.C., S. Pelan, J.T., A.T., J.W. and Kerstin Howe by WT206194; L.H., F.M., Kevin Howe and P. Flicek by WT108749/Z/15/Z, WT218328/B/19/Z and the European Molecular Biology Laboratory. O.F. and E.D.J. were supported by Howard Hughes Medical Institute and Rockefeller University start-up funds for this project. J.D. and H.A.L. were supported by the Robert and Rosabel Osborne Endowment. M.U.-S. received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (750747). F.T.-N., J. Hoffman, P. Masterson and K.C. were supported by the Intramural Research Program of the NLM, NIH. C.L., B.J.K., J. Kim and H.K. were supported by the Marine Biotechnology Program of KIMST, funded by the Ministry of Ocean and Fisheries, Republic of Korea (20180430). M.C. was supported by Sloan Research Fellowship (FG-2020-12932). S.C.V. was funded by a Max Planck Research Group award from the Max Planck Society, and a Human Frontiers Science Program (HFSP) Research grant (RGP0058/2016). T.M.L., W.E.J. and the Canada lynx genome were funded by the Maine Department of Inland Fisheries & Wildlife (F11AF01099), including when W.E.J. held a National Research Council Research Associateship Award at the Walter Reed Army Institute of Research (WRAIR). C.B. was supported by the NSF (1457541 and 1456612). D.B. was funded by The University of Queensland (HFSP - RGP0030/2015). D.I. was supported by Science Exchange Inc. (Palo Alto, CA). H.W.D. was supported by NSF grants (OPP-0132032 ICEFISH 2004 Cruise, PLR-1444167 and OPP-1955368) and the Marine Science Center at Northeastern University (416). G.J.P.N. and the thorny skate genome were funded by Lenfest Ocean Program (30884). M.P. was funded by the German Federal Ministry of Education and Research (01IS18026C). M. Malinsky was supported by an EMBO fellowship (ALTF 456-2016). The following authors' contributions were supported by the NIH: S. Selvaraj (R44HG008118); C.V.M., S.R.F., P.V.L. (R21 DC014432/DC/NIDCD); K.D.M. (R01GM130691); H.C. (5U41HG002371-19); M.D. (U41HG007234); and B.P. (R01HG010485). D.G. was supported by the National Key Research and Development Program of China (2017YFC1201201, 2018YFC0910504 and 2017YFC0907503). F.O.A. was supported by Al-Gannas Qatari Society and The Cultural Village Foundation-Katara, Doha, State of Qatar and Monash University Malaysia. C.T. was supported by The Rockefeller University. M. Hiller was supported by the LOEWE-Centre for Translational Biodiversity Genomics (TBG) funded by the Hessen State Ministry of Higher Education, Research and the Arts (HMWK). H.C. was supported by the NHGRI (5U41HG002371-19). R.H.S.K. was funded by the Max Planck Society with computational resources at the bwUniCluster and BinAC funded by the Ministry of Science, Research and the Arts Baden-Württemberg and the Universities of the State of Baden-Württemberg, Germany (bwHPC-C5). B.V. was supported by the Biomedical Research Council of A*STAR, Singapore. T.M.-B. was funded by the European Research Council under the European Union's Horizon 2020 research and innovation programme (864203), MINECO/FEDER, UE (BFU2017-86471-P), Unidad de Excelencia María de Maeztu, AEI (CEX2018-000792-M), a Howard Hughes International Early Career award, Obra Social "La Caixa" and Secretaria d'Universitats i Recerca and CERCA Programme del Departament d'Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880). E.C.T. was supported by the European Research Council (ERC-2012-StG311000) and an Irish Research Council Laureate Award. M.T.P.G. was supported by an ERC Consolidator Award 681396-Extinction Genomics, and a Danish National Research Foundation Center Grant (DNRF143). T.W. was supported by the NSF (1458652). J. M. Graves was supported by the Australian Research Council (CEO561477). E.W.M. was partially supported by the German Federal Ministry of Education and Research (01IS18026C). Complementary sequencing support for the Anna's hummingbird and several genomes was provided by Pacific Biosciences, Bionano Genomics, Dovetail Genomics, Arima Genomics, Phase Genomics, 10X Genomics, NRGene, Oxford Nanopore Technologies, Illumina, and DNAnexus. All other sequencing and assembly were conducted at the Rockefeller University, Sanger Institute, and Max Planck Institute Dresden genome labs. Part of this work used the computational resources of the NIH HPC Biowulf cluster (https://hpc.nih.gov). We acknowledge funding from the Wellcome Trust (108749/Z/15/Z) and the European Molecular Biology Laboratory. ; With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2018-000792-M). ; Peer reviewed

This study estimates how much tax revenue the European Union could collect by imposing a minimum tax on the profits of multinational companies. We compute the tax deficit of multinational firms, defined as the difference between what multinationals currently pay in taxes, and what they would pay if they were subject to a minimum tax rate in each country. We then consider three ways for EU countries to collect this tax deficit.First, we simulate an international agreement on a minimum tax of the type currently discussed by the OECD, favored by a number of European Union countries, and by the United States. In this scenario, each EU country would collect the tax deficit of its own multinationals. For instance, if the internationally agreed minimum tax rate is 25% and a German company has an effective tax rate of 10% on the profits it records in Singapore, then Germany would impose an additional tax of 15% on these profits to arrive at an effective rate of 25%. More generally, Germany would collect extra taxes so that its multinationals pay at least 25% in taxes on the profits they book in each country. Other nations would proceed similarly. We find that such a 25% minimum tax would increase corporate income tax revenues in the European Union by about €170 billion in 2021. This sum represents more than 50% of the amount of corporate tax revenue currently collected in the European Union and 12% of total EU health spending.The revenue potential of a coordinated minimum tax is thus large. However, revenues significantly depend on the commonly agreed minimum tax rate. With a 21% minimum rate, the European Union would collect about €100 billion in 2021. Moving from 21% to 15% would reduce the potential revenue by a factor of two to about €50 billion.Second, we simulate an incomplete international agreement in which only EU countries apply a minimum tax, while non-EU countries do not change their tax policies. In this scenario, each EU country would collect the tax deficit of its own multinationals (as in our first scenario), plus a portion of the tax deficit of multinationals incorporated outside of the European Union, based on the destination of sales. For instance, if a British company makes 20% of its sales in Germany, then Germany would collect 20% of the tax deficit of this company. We find that that in such a scenario, using a rate of 25% to compute the tax deficit of each multinational, the European Union would increase its corporate tax revenues about €200 billion. Out of this total, €170 billion would come from collecting the tax deficit of EU multinationals; an additional €30 billion would come from collecting a portion of the tax deficit of non-EU multinationals. For the European Union, there is thus a much higher revenue potential from increasing taxes on EU companies than from taxing non-EU companies.To improve the fairness of its tax system and generate new government revenues (e.g., to pay for the cost of Covid-19), it is essential that the European Union polices its own multinationals.Last, we estimate how much revenue each EU country could collect unilaterally, assuming all other countries keep their current tax policy unchanged. This corresponds to a "first-mover" scenario, in which one country alone decides to collect the tax deficit of multinational companies. This first mover would collect the full tax deficit of its own multinationals, plus a portion (proportional to the destination of sales) of the tax deficit of all foreign multinationals, based on a reference rate of 25%.We find that a first mover in the European Union would increase its corporate tax revenues by close to 70% relative to its current corporate tax collection. Although international coordination is always preferable, a unilateral move of a single EU member state (or a group of member states) would encourage other EU countries to also collect the tax deficit of multinationals—as not doing so would mean leaving tax revenues on the table for the first movers to grab. This could pave the way for an ambitious agreement on a high minimum tax, within the European Union and then globally. This analysis shows that unilateral action can play a transformative role and that refusing international coordination is not a sustainable solution, since other countries can always choose to collect the taxes that tax havens choose not to collect.Our estimates are based on a transparent methodology that combines newly available macroeconomic data on the location and effective tax rates of multinational profits.We illustrate and validate our approach by applying it to firm-level data publicly disclosed by all European banks and 16 large non-bank multinationals. We find that European banks would have to pay 41% more in taxes if they were subject to a 25% country-by-country minimum tax. This estimate is in line with our finding that EU multinationals as a whole (all sectors combined) would have to pay around 50% more in taxes, thus suggesting that this number is indeed the correct order of magnitude.Companies such as Shell, Iberdrola, and Allianz—who voluntarily disclose their country-by-country profits and taxes—would also have to pay 35%-50% more in taxes if they were subject to a 25% minimum tax.This report is supplemented by a pioneering interactive website, https://tax-deficitsimulator.herokuapp.com. This new tool allows policy makers, journalists, members of civil society, and all citizens in each EU country to assess the revenue potential from minimum taxation on both domestic and foreign firms. Users can select various scenarios (e.g., international coordination or unilateral action), and a full range of minimum tax rates from 10% to 50%. All the data and computer code are available online, making our estimates fully reproducible. We plan to regularly update our findings, as improved and more comprehensive macroeconomic data sources become available, refined estimation techniques are designed, and more companies publicly disclose their country-by-country reports.

This study estimates how much tax revenue the European Union could collect by imposing a minimum tax on the profits of multinational companies. We compute the tax deficit of multinational firms, defined as the difference between what multinationals currently pay in taxes, and what they would pay if they were subject to a minimum tax rate in each country. We then consider three ways for EU countries to collect this tax deficit.First, we simulate an international agreement on a minimum tax of the type currently discussed by the OECD, favored by a number of European Union countries, and by the United States. In this scenario, each EU country would collect the tax deficit of its own multinationals. For instance, if the internationally agreed minimum tax rate is 25% and a German company has an effective tax rate of 10% on the profits it records in Singapore, then Germany would impose an additional tax of 15% on these profits to arrive at an effective rate of 25%. More generally, Germany would collect extra taxes so that its multinationals pay at least 25% in taxes on the profits they book in each country. Other nations would proceed similarly. We find that such a 25% minimum tax would increase corporate income tax revenues in the European Union by about €170 billion in 2021. This sum represents more than 50% of the amount of corporate tax revenue currently collected in the European Union and 12% of total EU health spending.The revenue potential of a coordinated minimum tax is thus large. However, revenues significantly depend on the commonly agreed minimum tax rate. With a 21% minimum rate, the European Union would collect about €100 billion in 2021. Moving from 21% to 15% would reduce the potential revenue by a factor of two to about €50 billion.Second, we simulate an incomplete international agreement in which only EU countries apply a minimum tax, while non-EU countries do not change their tax policies. In this scenario, each EU country would collect the tax deficit of its own multinationals (as in our first scenario), plus a portion of the tax deficit of multinationals incorporated outside of the European Union, based on the destination of sales. For instance, if a British company makes 20% of its sales in Germany, then Germany would collect 20% of the tax deficit of this company. We find that that in such a scenario, using a rate of 25% to compute the tax deficit of each multinational, the European Union would increase its corporate tax revenues about €200 billion. Out of this total, €170 billion would come from collecting the tax deficit of EU multinationals; an additional €30 billion would come from collecting a portion of the tax deficit of non-EU multinationals. For the European Union, there is thus a much higher revenue potential from increasing taxes on EU companies than from taxing non-EU companies.To improve the fairness of its tax system and generate new government revenues (e.g., to pay for the cost of Covid-19), it is essential that the European Union polices its own multinationals.Last, we estimate how much revenue each EU country could collect unilaterally, assuming all other countries keep their current tax policy unchanged. This corresponds to a "first-mover" scenario, in which one country alone decides to collect the tax deficit of multinational companies. This first mover would collect the full tax deficit of its own multinationals, plus a portion (proportional to the destination of sales) of the tax deficit of all foreign multinationals, based on a reference rate of 25%.We find that a first mover in the European Union would increase its corporate tax revenues by close to 70% relative to its current corporate tax collection. Although international coordination is always preferable, a unilateral move of a single EU member state (or a group of member states) would encourage other EU countries to also collect the tax deficit of multinationals—as not doing so would mean leaving tax revenues on the table for the first movers to grab. This could pave the way for an ambitious agreement on a high minimum tax, within the European Union and then globally. This analysis shows that unilateral action can play a transformative role and that refusing international coordination is not a sustainable solution, since other countries can always choose to collect the taxes that tax havens choose not to collect.Our estimates are based on a transparent methodology that combines newly available macroeconomic data on the location and effective tax rates of multinational profits.We illustrate and validate our approach by applying it to firm-level data publicly disclosed by all European banks and 16 large non-bank multinationals. We find that European banks would have to pay 41% more in taxes if they were subject to a 25% country-by-country minimum tax. This estimate is in line with our finding that EU multinationals as a whole (all sectors combined) would have to pay around 50% more in taxes, thus suggesting that this number is indeed the correct order of magnitude.Companies such as Shell, Iberdrola, and Allianz—who voluntarily disclose their country-by-country profits and taxes—would also have to pay 35%-50% more in taxes if they were subject to a 25% minimum tax.This report is supplemented by a pioneering interactive website, https://tax-deficitsimulator.herokuapp.com. This new tool allows policy makers, journalists, members of civil society, and all citizens in each EU country to assess the revenue potential from minimum taxation on both domestic and foreign firms. Users can select various scenarios (e.g., international coordination or unilateral action), and a full range of minimum tax rates from 10% to 50%. All the data and computer code are available online, making our estimates fully reproducible. We plan to regularly update our findings, as improved and more comprehensive macroeconomic data sources become available, refined estimation techniques are designed, and more companies publicly disclose their country-by-country reports.

2-s2.0-85063267754 ; A search for the pair production of heavy fermionic partners of the top quark with charge 5/3 (X 5/3 ) is performed in proton-proton collisions at a center-of-mass energy of 13 TeV with the CMS detector at the CERN LHC. The data sample analyzed corresponds to an integrated luminosity of 35.9 fb ?1 . The X 5/3 quark is assumed always to decay into a top quark and a W boson. Both the right-handed and left-handed X 5/3 couplings to the W boson are considered. Final states with either a pair of same-sign leptons or a single lepton are studied. No significant excess of events is observed above the expected standard model background. Lower limits at 95% confidence level on the X 5/3 quark mass are set at 1.33 and 1.30 TeV respectively for the case of right-handed and left-handed couplings to W bosons in a combination of the same-sign dilepton and single-lepton final states.[Figure not available: see fulltext.] © 2019, The Author(s). ; 30820817 2012/07/E/ST2/01406, 2014/13/B/ST2/02543, 2014/14/M/ST2/00428, 2014/15/B/ST2/03998, 2015/19/B/ST2/02861 National Science Foundation, NSF: 1806415 U.S. Department of Energy, USDOE Welch Foundation: C-1845 Hispanics in Philanthropy, HIP CS Fund, CSF American Friends of the Alexander von Humboldt Foundation, AFAvH California Earthquake Authority, CEA Qatar National Research Fund, QNRF Secretaría de Educación Pública, SEP Türkiye Atom Enerjisi Kurumu, TAEK Horizon 2020 Framework Programme, H2020: 675440 Weston Havens Foundation Louisiana Academy of Sciences, LAS Missouri University of Science and Technology, MST CERN College of Arts and Sciences, University of Nebraska-Lincoln, CAS Norwegian Sequencing Centre, NSC Institute for the Promotion of Teaching Science and Technology, IPST Mountain Equipment Co-operative, MEC Science and Technology Facilities Council, STFC: ST/N000242/1 Royal Astronomical Society, RAS European Commission, EC European Research Council, ERC Ministry of Education - Singapore, MOE Department of Atomic Energy, Government of India, ???? Science Foundation Ireland, SFI Helmholtz-Gemeinschaft, HGF Deutsche Forschungsgemeinschaft, DFG Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP National Natural Science Foundation of China, NSFC Research Promotion Foundation, ???? Ministerstvo Školství, Mláde?e a T?lov?chovy, MŠMT Fundacja na rzecz Nauki Polskiej, FNP Fundação para a Ciência e a Tecnologia, FCT Russian Foundation for Basic Research, ???? Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES Academy of Finland Bundesministerium für Bildung und Forschung, BMBF Austrian Science Fund, FWF Fonds De La Recherche Scientifique - FNRS, FNRS Belgian Federal Science Policy Office, BELSPO Chulalongkorn University, CU Fonds Wetenschappelijk Onderzoek, FWO Agentschap voor Innovatie door Wetenschap en Technologie, IWT Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture, FRIA Consejo Nacional de Ciencia y Tecnología, CONACYT Bundesministerium für Wissenschaft, Forschung und Wirtschaft, BMWFW General Secretariat for Research and Technology, GSRT Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq Ministry of Science, ICT and Future Planning, MSIP Ministry of Science and Technology, MOST National Research Foundation of Korea, NRF Joint Institute for Nuclear Research, JINR Magyar Tudományos Akadémia, MTA Instituto Nazionale di Fisica Nucleare, INFN A.G. Leventis Foundation National Science and Technology Development Agency, ????: Thailand Secretaría de Educación Superior, Ciencia, Tecnología e Innovación, SENESCYT Universiti Malaya, UM Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, FAPERJ Ministry for Business Innovation and Employment, MBIE National Academy of Sciences of Ukraine, NASU Ministry of Education and Science, MES Institute for Research in Fundamental Sciences, IPM Benemérita Universidad Autónoma de Puebla, BUAP Secretaría de Estado de Investigación, Desarrollo e Innovación, SEIDI Comisión Asesora de Investigación Científica y Técnica, CAICYT: MDM-2015-0509 Horizon 2020 European Regional Development Fund, FEDER State Atomic Energy Corporation ROSATOM, ROSATOM Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, CINVESTAV Pakistan Atomic Energy Commission, PAEC State Fund for Fundamental Research of Ukraine, SFFR Department of Science and Technology, Government of West Bengal, DST Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA: 123842, 123959, 124845, 124850, 125105 ; We congratulate our colleagues in the CERN accelerator departments for the excellent performance of the LHC and thank the technical and administrative staffs at CERN and at other CMS institutes for their contributions to the success of the CMS effort. In addition, we gratefully acknowledge the computing centres and personnel of the Worldwide LHC Computing Grid for delivering so effectively the computing infrastructure essential to our analyses. Finally, we acknowledge the enduring support for the construction and operation of the LHC and the CMS detector provided by the following funding agencies: BMWFW and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COL-CIENCIAS (Colombia); MSES and CSF (Croatia); RPF (Cyprus); SENESCYT (Ecuador); MoER, ERC IUT, and ERDF (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); NKFIA (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); MSIP and NRF (Republic of Korea); LAS (Lithuania); MOE and UM (Malaysia); BUAP, CINVESTAV, CONACYT, LNS, SEP, and UASLP-FAI (Mexico); MBIE (New Zealand); PAEC (Pakistan); MSHE and NSC (Poland); FCT (Portugal); JINR (Dubna); MON, RosAtom, RAS and RFBR (Russia); MESTD (Serbia); SEIDI, CPAN, PCTI and FEDER (Spain); Swiss Funding Agencies (Switzerland); MST (Taipei); ThEPCenter, IPST, STAR, and NSTDA (Thailand); TUBITAK and TAEK (Turkey); NASU and SFFR (Ukraine); STFC (United Kingdom); DOE and NSF (U.S.A.). ; Individuals have received support from the Marie-Curie programme and the European Research Council and Horizon 2020 Grant, contract No. 675440 (European Union); the Leventis Foundation; the A.P. Sloan Foundation; the Alexander von Humboldt Founda- ; Open Access, Copyright CERN, for the benefit of the CMS Collaboration. Article funded by SCOAP3.

In the lowlands of Ethiopia, the traditionally pastoralist Afar and Somali Regions, multifaceted transformations and commodification processes have taken place. This thesis focuses on these transformations by addressing their fundamental societal, economic, and environmental developments. Three papers were written to clearly demonstrate how such environmental, political, social and economic processes have shaped and continue to alter and impact Afar and Somali communities in Eastern Ethiopia. The first paper, Pastoral livelihoods under pressure: Ecological, political and socioeconomic transitions in Afar (Ethiopia) by Matthias Schmidt (lead author) and Olivia Pearson (2016) and published by the Journal of Arid Environments 124, 22-30, will be referred to as "Pastoral livelihoods under pressure" from this point forward. It addresses the various ecological, political and socio-economic changes currently transforming the rangelands and natural resources of the Afar pastoralists' ancestral domain, changes which are driven by factors such as recurrent droughts, overgrazing, erosion processes, alien plant invasion and governmental land policies. To assess how these inter-related changes are impacting the Afar and their livelihoods, empirical research was conducted in four villages in western Afar, with the results showing that environmental, institutional and cultural changes have weakened the position of the pure pastoralist and strengthened the move away from pure pastoralism towards agro-pastoralism. As introduced natural resource management strategies driven by land privatization alter common property resources, traditional practices and institutions lose power. While research clearly shows that the influence and control of indigenous institutions and cultural practices have diminished, the subsequent impact on future generations and Afar identity remains unclear. The second paper, by Olivia Pearson (lead author) and Matthias Schmidt (2017) Repercussions of Governance Institutional Changes on Communication Practices in Afar, Ethiopia has been accepted by the Singapore Journal of Tropical Geography and will be referred to as "Governance Institutional Changes" from this point forward. By examining local communication practices, this paper investigates the transition from informal and traditional Afar institutions to formal institutions occurring in the Afar Region of Ethiopia. As the role and importance of traditional institutions diminishes and the strength of introduced formal federal and regional governmental institutions increases, pastoralist and agro-pastoralists in western Afar have altered how and with whom they communicate. The decrease in traditional ecological, political and socio-economic settings has led to the Afar adapting their communication practices in order to navigate these new environments. An analysis conducted from empirical research conducted in four Afar villages illustrates changes in resident preferences when reporting concerns. Concerns are now primarily reported to local formal institutional representatives or government agents; however, residents still find it beneficial to report certain problems and concerns to traditional institutions. This transition has had a positive impact on females, who now report concerns directly to government officials. Conversely, the transition has spatial disadvantages due to the typical location of government officials in village and town centers; as Afar is a vast and lowly populated region, those residing further from their government representative are at a disadvantage. The final paper, by Olivia Pearson (lead author) and Matthias Schmidt (2017) Commodity Individuation of Milk in the Somali Region, Ethiopia has been accepted by Area and will be referred to as "Milk Commodity Individuation" from this point forward. This paper analyses one of the changes to livestock commodification in the Somali region of Ethiopia – the extent and implications of altering the social and cultural role of milk. Traditionally, livestock is a central Somali commodity, with herds specifically chosen for their ability to reside within the arid to semi-arid region and sustain pastoralist livelihoods. Somalis sell livestock and consume their meat and milk, which is a fundamental requirement for a healthy life; milk provides sustenance in an environment where resources are scarce and is also a traditional medicine. The commodity individuation of milk means that it is now sold by Somalis as an income generating tool, defying cultural traditions that declared the sale of milk to be taboo. Milk has been separated from its traditional function and context and is no longer solely food for livestock and Somalis but now also a source of income that is primarily managed by females. Traditional milk boundaries have been stretched and altered, with the commodity now managed through the informal relationships between buyers and sellers. To investigate the correlations between the three papers, each of which has its own unique theoretical framework, this booklet uses the results of the conducted research as indicators to identify the prevalent transformations and commodification processes present in the lowlands of Ethiopia. Castree's (2003) six distinct and inter-related elements of capitalist commodification – Privatisation, Individuation, Alienability, Abstraction, Valuation, and Displacement – are used for the data analysis. The discussion is divided into three categories, the first being the transformation and commodification of clan structures to highlight the juxtaposed valuation and devaluation of these structures. As the clan as an institution is replaced by formal institutions, its control over environmental, societal, and cultural management weakens. This devaluation occurs in parallel with the valuation assimilation of clan leaders and elders into formal institutions and as the clan as a commodity faces displacement, in particular the clan leader. The transformation and commodification of gender highlights the shift in gendered roles for both sexes and the increase in female mobility, with the sale of milk and other income generating activities fundamental to this transition. A shift in control over household management from male to female has occurred and has been supported by perceived female altruism. The final section deals with natural resources and their management and focuses on the key related transition and commodification practice – the privatisation of land and its resulting environmental and societal consequences. In conclusion, it is important to note that while these areas have become increasingly integrated into global systems, leaving behind many traditional institutions, the mentioned transformations and commodification processes will continue to evolve. Findings suggest that the Somali and Afar Regions will become increasingly influenced by outside forces and institutions, which will drive further change in the lives and livelihood practices of the lowland residents of Ethiopia's arid and semi-arid regions.

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