Suchergebnisse

ACKNOWLEDGEMENTS We are grateful to the families who took part in GS:SFHS, the GPs and Scottish School of Primary Care for their help in recruiting them, and the whole GS team, which includes academic researchers, clinic staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers. This work is supported by the Wellcome Trust through a Strategic Award, reference 104036/Z/14/Z. The Chief Scientist Office of the Scottish Government and the Scottish Funding Council provided core support for Generation Scotland. GS:SFHS was funded by a grant from the Scottish Government Health Department, Chief Scientist Office, number CZD/16/6. We acknowledge with gratitude the financial support received for this work from the Dr Mortimer and Theresa Sackler Foundation. PT, DJP, IJD, and AMM are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council is gratefully acknowledged. ; Peer reviewed ; Publisher PDF

Acknowledgements This research was made possible due to the infrastructure and funding provided by the Scottish Genomes Partnership, for which we are grateful. We thank the members of the Scottish Genomes Partnership Ethics Advisory Group (in particular the Chair Dr Anne Lampe) for their suggestions for improvement and constructive criticisms of the project. The University of Edinburgh Academic and Clinical Central Office for Research and Development (ACCORD) also provided helpful advice. VIKING DNA extractions and array genotyping were performed at the Edinburgh Clinical Research Facility, University of Edinburgh and were funded by the Medical Research Council UK quinquennial programme grant to the MRC Human Genetics Unit. Emily Weiss and Reka Nagy assembled the Shetland pedigree using records kept at the General Register Ofce and study information, building on earlier pedigree work in the Northern Isles. Nicola Pirastu selected the most appropriate participants for WGS using the ANCHAP software. Whole Genome Sequencing was carried out at Edinburgh Genomics, The University of Edinburgh. We thank Susan Campbell and technical services at MRC HGU for the Sanger sequencing. We thank Archie Campbell and Rachel Edwards for transfer of ECG data into an SQL database and for expert support with extraction of EHR data. Te linkage to data in the EHR provided by patients and collected by the NHS as part of their care and support was facilitated by Dionysis Vragkos, eData Research and Innovation Service (eDRIS). We would like to acknowledge the invaluable contributions of the research nurses in Shetland and the administrative team in Edinburgh. Finally and most importantly, we thank the people of Shetland for their involvement in and ongoing support for our research. This work was funded by the MRC University Unit award to the MRC Human Genetics Unit, University of Edinburgh, MC_UU_00007/10. Whole genome sequencing was funded by the Chief Scientist Office of the Scottish Government Health Directorates (grant reference ...

Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to individual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish individuals were selected for high scores on a general component of intelligence (g). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g. Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g. The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g. Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger samples would be worthwhile.

Generation Scotland has received core funding from the Chief Scientist Office of the Scottish Government Health DirectoratesCZD/16/6 and the Scottish Funding CouncilHR03006. We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the UK's Medical Research Council. The Quantitative Trait Locus team at the Human Genetics Unit is funded by the Medical Research Council. REM, GD, DL, ML, DJP, PMV, and IJD undertook the work within The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (MR/K026992/1), part of the cross council Lifelong Health and Wellbeing Initiative. Funding from the BBSRC and MRC is gratefully acknowledged. REM is an Alzheimer's Research UK Fellow (ART-RF2010-2). ; Peer reviewed ; Publisher PDF

Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award "STratifying Resilience and Depression Longitudinally" (STRADL) Reference 104036/Z/14/Z. YZ acknowledges support from China Scholarship Council. IJD is supported by the Centre for Cognitive Ageing and Cognitive Epidemiology which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). AMMcI and T-KC acknowledges support from the Dr Mortimer and Theresa Sackler Foundation. We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Ethics approval for the study was given by the NHS Tayside committee on research ethics (reference 05/S1401/8) ; Peer reviewed ; Publisher PDF

Acknowledgements We are grateful to the families who took part in GS:SFHS, the GPs and Scottish School of Primary Care for their help in recruiting them, and the whole GS team, which includes academic researchers, clinic staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers. Funded by Scottish Government Health Department, Chief Scientist Office. Grant Number: CZD/16/6 National Institutes of Health. Grant Numbers: N01-HG-65403, HHSN268200782096C, RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, P50 AA12870, MSTP T32GM07205, CTSA 8UL1TR000142 NIH Genes, Environment and Health Initiative [GEI]. Grant Numbers: U01 HG004422, U01HG004438 Gene Environment Association Studies (GENEVA). Grant Number: U01 HG004446 Collaborative Study on the Genetics of Alcoholism. Grant Number: U10 AA008401 Collaborative Genetic Study of Nicotine Dependence. Grant Number: P01 CA089392 Family Study of Cocaine Dependence. Grant Number: R01 DA013423 National Institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse Dr Mortimer and Theresa Sackler Foundation Biotechnology and Biological Sciences Research Council (BBSRC) Medical Research Council (MRC) ; Peer reviewed ; Publisher PDF

This work is supported by the Wellcome Trust through a Strategic Award, reference 104036/Z/14/Z. GS:SFHS was funded by a grant from the Scottish Government Health Department, Chief Scientist Office, number CZD/16/6. The authors acknowledge with gratitude the financial support received for this work from the Dr. Mortimer and Theresa Sackler Foundation. PAT, DJP and AMM are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged by PN and CSH (BB/J004235/1). DJM is an NRS Fellow, funded by the CSO. ; Peer reviewed ; Publisher PDF

This project was funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). L.S is funded by the Virtual Brain Cloud from European comission (grant no. H2020-SC1-DTH-2018-1). C.R.B is funded by National Institutes of Health (NIH) research grant R01AG054628. S.R.C is funded by National Institutes of Health (NIH) research grant (R01AG054628), Medical Research Council (MR/R024065/1), Age UK and Economic and Social Research Council. R.E.M. was supported by Alzheimer's Research UK major project grant ARUKPG2017B-10. C.H was supported by an MRC Human Genetics Unit programme grant "Quantitative traits in health and disease" (U.MC_UU_00007/10). H.C.W received funding from Wellcome Trust. J.W is funded by TauRx pharmaceuticals Ltd and received Educational grant from Biogen paid to Alzheimer Scotland/Brain Health Scotland. G.W received GRAMPIAN UNIVERSITY HOSPITALS NHS TRUST, Scottish Government—Chief Scientist Office, ROLAND SUTTON ACADEMIC TRUST, Medical Research Scotland, Sutton Academic Trust and ROLAND SUTTON ACADEMIC TRUST. J.M.W received Wellcome Trust Strategic Award, MRC UK Dementia Research Institute and MRC project grants, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant (666881). D.S received MRC (MR/S010351/1), MRC (MR/W002388/1) and MRC (MR/W002566/1). A.M is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z) and UKRI MRC (MC_PC_17209, MR/S035818/1). This work is part of a project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776. In addition, A.M has received grant support from The Sackler Trust, outside of the work presented. N.B received grant to institution from GSK as part of GSK/Oxford FxG initiative. A.N.H received John Black Charitable Fund-Rosetrees, H2020 funding from European Comission-Project Virtual Brain Cloud, AI for the Discovery of new therapies in Parkinson's (A2926), Rising Start Initiative—stage 2, Brain-Gut Microbiome (Call: PAR-18-296; Award ID: 1U19AG063744-01), Gut-liver-brain biochemical axis in Alzheimer's disease (5RF1AG057452-01), Virtual Brain Cloud (Call: H2020-SC1-DTH- 2018-1; Grant agreement ID: 826421). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award "STratifying Resilience and Depression Longitudinally" [STRADL] Reference 104036/Z/14/Z). We are grateful to all the families who took part; the general practitioners and the Scottish School of Primary Care for their help in recruiting them; and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants, and nurses. ; Peer reviewed ; Publisher PDF

For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates. ; Generation Scotland: Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of the GS:SFHS samples was carried out by the Genetics ...

This work was supported by the Wellcome Trust through a Strategic Award Reference No. 104036/Z/14/Z, the Dr. Mortimer and Theresa Sackler Foundation (T-KC and AMM), the Medical Research Council (MRC) to the Human Genetics Unit (PN and CSH), and the Biotechnology and Biological Sciences Research Council Grant No. BB/J004235/1 (PN and CSH). The Chief Scientist Office of the Scottish Government and the Scottish Funding Council provided core support for Generation Scotland (GS). GS: The Scottish Family Health Study (SFHS) was funded by a grant from the Scottish Government Health Department, Chief Scientist Office, No. CZD/16/6. This work was also supported by National Institutes of Health Grant No. UO1MH105630. We thank the families who took part in GS:SFHS, the general practitioners, and Scottish School of Primary Care for their help in recruiting them, and the whole GS team, which includes academic researchers, clinic staff, laboratory technicians, clerical workers, information technology staff, statisticians, and research managers. YZ thanks Mr. Ian White for the suggestion for analysis of polygenic score. AMF-P, LSH, BHS, LJH, SP, CH, and NRW report no biomedical financial interests or potential conflicts of interest. YZ received support from China Scholarship Council. PN and CSH received support from the MRC. T-KC and AMM received financial support for this work from the Dr. Mortimer and Theresa Sackler Foundation. PAT, IJD, DJP, and AMM are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). DJM is an NRS (National Health Service Research Scotland) Fellow, funded by the Chief Scientist Office. AMM previously received grant support from Pfizer, Lilly, and Janssen; those studies are not connected to the present investigation. ; Peer reviewed ; Publisher PDF

Acknowledgments and Disclosures: This work was supported by the Wellcome Trust through a Strategic Award (104036/Z/14/Z). The Chief Scientist Office of the Scottish Government and the Scottish Funding Council provided core support for Generation Scotland. GS:SFHS was funded by a grant from the Scottish Government Health Department, Chief Scientist Office (CZD/16/6). We are grateful to the families who took part in GS:SFHS, the general practitioners and Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes academic researchers, clinic staff members, laboratory technicians, clerical workers, information technology staff members, statisticians, and research managers. AMM has previously received grant support from Pfizer, Lilly, and Janssen. These studies are not connected to the current investigation. YZ acknowledges support from the China Scholarship Council. T-KC and AMM acknowledge with gratitude the financial support received for this work from the Dr Mortimer and Theresa Sackler Foundation. PAT, DJP, IJD, and AMM are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council (MRC) is gratefully acknowledged. DJM is an NHS Research Scotland (NRS) Fellow, funded by the Chief Scientist Office. PN and CSH acknowledge support from the MRC. All other authors report no biomedical financial interests or potential conflicts of interest. GS:SFHS data are available to researchers on application to the Generation Scotland Access Committee (access: http://generationscotland.org). The managed access process ensures that approval is granted only to research that comes under the terms of participant consent. ; Peer reviewed ; Publisher PDF

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files ; Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population. ; European Union's Seventh Framework Programme Medical Research Council (MRC) Centre European Community's Seventh Framework Programme German Research Foundation (DFG) Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Munster National Health and Medical Research Council (NHMRC) Agencia Estatal de Investigacion (AEI) Xunta de Galicia Fondo Europeo de Desarrollo Regional (FEDER) Lundbeck Foundation Stanley Medical Research Institute, an advanced grant from the European Research Council Danish Strategic Research Council Aarhus University Wellcome Trust Juvenile Diabetes Research Foundation (JDRF) European Union National Institute for Health Research (NIHR) programme Chief Scientist Office of the Scottish government Health Directorates Scottish Funding Council National Institute of ...

The PGC was funded by National Institute of Mental Health (NIMH) Grant Nos. MH085520 (to PFS) and MH080403. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization Grant No. NWO 480-05-003 (to D. Posthuma) and the department of Psychology, Vrije Universiteit Amsterdam along with a supplement from the Dutch Brain Foundation. The Bonn/Mannheim GWAS was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia Grant Nos. 01GS08144 and 01GS08147, under the auspices of the National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders, under the auspices of the e:Med Programme Grant Nos. 01ZX1314A and 01ZX1314G. The Bonn/Mannheim GWAS was also supported by the German Research Foundation (DFG) Grant Nos. FOR2107, RI908/11-1, and NO246/10-1. The GenRED GWAS project was supported by NIMH R01 Grant Nos. MH061686 (to DFL), MH059542 (to W.H. Coryell), MH075131 (W.B. Lawson), MH059552 (JBP), MH059541 (W.A. Scheftner), and MH060912 (MMW). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression by Grant No. 01ES0811. Genotyping was supported by the Bavarian Ministry of Commerce, and the BMBF in the framework of the National Genome Research Network by Grant Nos. NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145. The Netherlands Study of Depression and Anxiety and the Netherlands Twin Register contributed to Genetic Association Information Network (GAIN)-MDD and to MDD2000. Funding for NTR/NESDA was from the following: the Netherlands Organization for Scientific Research (MagW/ZonMW Grant Nos. 904-61-090, 985-10- 002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie Grant No. 56-464-14192; Geestkracht program Grant No. 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, Vrije Universiteit's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, BIC/BioAssist/RK (Grant No. 2008.024); the European Science Foundation (Grant No. EU/QLRT-2001-01254); the European Community's Seventh Framework Program (Grant No. FP7/2007-2013); ENGAGE (Grant No. HEALTH-F4-2007-201413); and the European Science Council (Grant No. ERC 230374). Genotyping was funded in part by the GAIN of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (Grant No. MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (Grant Nos. 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (Grant Nos. FT0991360, FT0991022), the FP-5 GenomEUtwin Project (Grant No. QLG2-CT-2002-01254), and the US National Institutes of Health (Grant Nos. AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD). RADIANT was funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (Grant No. G0701420); the National Institute for Health Research Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and the Institute of Psychiatry, King's College London; the UK Medical Research Council (Grant No. G0000647), and the Marie Curie Industry-Academia Partnership and Pathways (Grant No. 286213). The GENDEP study was funded by a European Commission Framework 6 grant (EC Contract Ref.: LSHB-CT-2003-503428). Genotyping of STAR*D was supported by NIMH Grant No. MH072802 (to SPH). STAR*D was funded by NIMH Grant No. N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (to A.J. Rush). The CoLaus/PsyCoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (Grant Nos. 3200B0–105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401) and two grants from GlaxoSmithKline Clinical Genetics. 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 (Grant Nos. 01ZZ9603, 01ZZ0103, 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg–West Pomerania. 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. SHIP-LEGEND is funded by the DFG (Grant No. GR 1912/5-1). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (Grant No. M-2005-1112), GenomEUtwin (Grant Nos. EU/QLRT-2001-01254, QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (Grant No. U01 DK066134). The collection of PRISME control subjects and genotyping of the 883 Danish control subjects was supported by grants from The Danish Strategic Research Council, The Stanley Research Foundation, and H. Lundbeck A/S. The Muenster Depression cohorts were supported by the European Union (Grant No. N Health-F2-2008-222963) and by grants from the DFG (Grant Nos. FOR 2107 and DA1151/5-1 [to UD]), Innovative Medizinische Forschung of the Medical Faculty of Mu¨nster (Grant Nos. DA120903, DA111107, and DA211012 [all to UD]). Generation Scotland is supported by a Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" (Reference No.: 104036/Z/14/Z) and core support from the Chief Scientist Office of the Scottish Government Health Directorates (Grant No. CZD/16/6) and the Scottish Funding Council (Grant No. HR03006). Supplementary material cited in this article is available online at http:// dx.doi.org/10.1016/j.biopsych.2016.05.010. ; Peer reviewed ; Publisher PDF

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. Acknowledgements: We especially thank all volunteers who participated in our study. This study made use of data generated by the 'Genome of the Netherlands' project, which is funded by the Netherlands Organization for Scientific Research (grant no. 184021007). The data were made available as a Rainbow Project of BBMRI-NL. Samples were contributed by LifeLines (http://lifelines.nl/lifelines-research/general), the Leiden Longevity Study (http://www.healthy-ageing.nl; http://www.langleven.net), the Netherlands Twin Registry (NTR: http://www.tweelingenregister.org), the Rotterdam studies (http://www.erasmus-epidemiology.nl/rotterdamstudy) and the Genetic Research in Isolated Populations programme (http://www.epib.nl/research/geneticepi/research.html#gip). The sequencing was carried out in collaboration with the Beijing Institute for Genomics (BGI). Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 and HL103612 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. The CROATIA cohorts would like to acknowledge the invaluable contributions of the recruitment teams in Vis, Korcula and Split (including those from the Institute of Anthropological Research in Zagreb and the Croatian Centre for Global Health at the University of Split), the administrative teams in Croatia and Edinburgh and the people of Vis, Korcula and Split. SNP genotyping was performed at the Wellcome Trust Clinical Research Facility in Edinburgh for CROATIA-Vis, by Helmholtz Zentrum München, GmbH, Neuherberg, Germany for CROATIA-Korcula and by AROS Applied Biotechnology, Aarhus, Denmark for CROATIA-Split. They would also like to thank Jared O'Connell for performing the pre-phasing for all cohorts before imputation. The ERF study as a part of EuroSPAN (European Special Populations Research Network) was supported by European Commission FP-6 STRP grant number 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 joint grant from the Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). This research was financially supported by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007). Statistical analyses for the ERF study 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 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. The FamHS is funded by a NHLBI grant 5R01HL08770003, and NIDDK grants 5R01DK06833603 and 5R01DK07568102. The Framingham Heart Study SHARe Project for GWAS scan was supported by the NHLBI Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix Inc for genotyping services (Contract No. N02-HL-6-4278). DNA isolation and biochemistry were partly supported by NHLBI HL-54776. 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 the Boston University School of Medicine and Boston Medical Center. We are grateful to Han Chen for conducting the 1000G imputation. The Family Heart Study was supported by the by grants R01-HL-087700 and R01-HL-088215 from the National Heart, Lung, and Blood Institute (NHLBI). We would like to acknowledge the invaluable contributions of the families who took part in the Generation Scotland: Scottish Family Health Study, the general practitioners and Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes academic researchers, IT staff, laboratory technicians, statisticians and research managers. SNP genotyping was performed at the Wellcome Trust Clinical Research Facility in Edinburgh. GS:SFHS is funded by the Scottish Executive Health Department, Chief Scientist Office, grant number CZD/16/6. SNP genotyping was funded by the Medical Research Council, United Kingdom. We wish to acknowledge the services of the LifeLines Cohort Study, the contributing research centres delivering data to LifeLines and all the study participants. MESA Whites and the MESA SHARe project are conducted and supported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the NHLBI. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02.HL.6.4278. MESA Family is conducted and supported in collaboration with MESA investigators; support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258 and R01HL071259. We thank the participants of the MESA study, the Coordinating Center, MESA investigators and study staff for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Netherland Twin Register (NTR) and Netherlands Study of Depression and Anxiety (NESDA): Funding was obtained from the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants Middelgroot-911-09-032, Spinozapremie 56-464-14192, Geestkracht programme of the Netherlands Organization for Health Research and Development (Zon-MW, grant number 10-000-1002), Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL, 184.021.007), VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community's Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC Advanced, 230374); and the European Research Council (ERC-284167). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant 2R01LM010098), The Netherlands Organisation for Health Research and Development (NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70, ZonMw grant 90.700.441) and the Dutch Inter University Cardiology Institute Netherlands (ICIN). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. J.W.J is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Genotyping was supported by the seventh framework programme of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). 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. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 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)/Netherlands Organisation for Scientific Research (NWO) project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their help in creating the GWAS database. ; Peer reviewed ; Publisher PDF

Publisher's version (útgefin grein) ; Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D. ; 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 HHSN268201100046C, HSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The grant funding of WHI are R21 HL123677, R56 DK104806 and R01 MD012765 to NF. The FamHS was funded by R01HL118305 and R01HL117078 NHLBI grants, and 5R01DK07568102 and 5R01DK089256 NIDDK grant." and "The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (project # Z01-AG000513 and human subjects protocol number 09-AGN248). Support for GENOA was provided by the National Heart, Lung and Blood Institute (HL119443, HL087660, HL054464, HL054457, and HL054481) of the National Institutes of Health. Ruth loos is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). The Rotterdam Study GWAS datasets are supported 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), and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 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). The ERF study was further supported by ENGAGE consortium and CMSB. Highthroughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWORFBR 047.017.043).ERF was further supported by the ZonMw grant (project 91111025), and this work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6- 4278). This study is also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to Drs. Meigs, Dupuis and Florez, NIDDK K24 DK080140 to Dr. Meigs, and a Doris Duke Charitable Foundation Clinical Scientist Development Award to Dr. Florez. The HERITAGE Family Study was supported by National Heart, Lung, and Blood Institute grant HL-45670. The Women's Genome Health Study is supported by the National Heart, Lung, and Blood Instutute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913). Additional support for endpoint collection was provided by the National Heart, Lung, and Blood Institute under ARRA funding (HL099355). HyperGEN (Hypertension Genetic Epidemiology Network): The hypertension network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and 2 R01 HL55673- 12. The AGES study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease)"and "Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6, the Scottish Funding Council HR03006 and the Wellcome Trust through a Strategic Award (reference 104036/Z/14/Z) for Stratifying Resilience and Depression Longitudinally (STRADL). Genotyping was funded by the UK's Medical Research Council. Jose C. Florez, NIDDK K24 DK110550 The MESA project is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Additionally, one or more authors are affiliated with the following commercial entities: Interleukin Genetics, GlaxoSmithKline, Daiichi-Sankyo, AstraZeneca, Data Tecnica International LLC, Illumina Inc., University of California Healthcare, Janssen Pharmaceuticals, Goldfinch Bio, and Novo Nordisk. Please see the Competing Interests Statement for additional details. The funders provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. ; Peer Reviewed