Suchergebnisse

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches. ; This work has been sponsored by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III and Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR). Sílvia Bonàs was FI-DGR Fellowship from FI-DGR 2013 from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya). This study makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. This study also makes use of data generated by the UK10K Consortium, derived from samples from UK10K COHORT IMPUTATION (EGAS00001000713). A full list of the investigators who contributed to the generation of the data is available in www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We acknowledge PRACE for awarding us to access MareNostrum supercomputer, based in Spain at Barcelona. The technical support group, particularly Pablo Ródenas and Jorge Rodríguez, from the Barcelona Supercomputing Center is gratefully acknowledged. This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 667191. Mercè Planas-Fèlix is funded by the Obra Social Fundación la Caixa fellowship under the Severo Ochoa 2013 program. Work from Irene Miguel-Escalada, Ignasi Moran, Goutham Atla, and Jorge Ferrer was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, the Wellcome Trust (WT101033), Ministerio de Economía y Competitividad (BFU2014-54284-R) and Horizon 2020 (667191). Irene Miguel-Escalada has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska–Curie grant agreement No 658145. We acknowledge Prof. Giulio Cossu (Institute of Inflammation and Repair, University of Manchester) for providing the muscle myoblast cell line. We also acknowledge the InterAct and SIGMA Type 2 Diabetes Consortia for access to the data to replicate the rs146662075 variant. A full list of the investigators of the SIGMA Type 2 Diabetes and the InterAct consortia is provided in Supplementary Notes 3 and 4. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). This research has been conducted using the UK Biobank Resource (application number 16803). We also acknowledge Bianca C. Porneala, MS for his technical assistance in the collection and curation of the genotype and phenotype data from Partners Biobank. We also thank Marcin von Grotthuss for their support for uploading the summary statistics data to the Type 2 Diabetes Genetic Portal (AMP-T2D portal). Finally, we thank all the Computational Genomics group at the BSC for their helpful discussions and valuable comments on the manuscript. ; Peer Reviewed ; Postprint (published version)

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches. ; This work has been sponsored by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III and Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR). Sílvia Bonàs was FI-DGR Fellowship from FI-DGR 2013 from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya). This study makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. This study also makes use of data generated by the UK10K Consortium, derived from samples from UK10K COHORT IMPUTATION (EGAS00001000713). A full list of the investigators who contributed to the generation of the data is available in www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We acknowledge PRACE for awarding us to access MareNostrum supercomputer, based in Spain at Barcelona. The technical support group, particularly Pablo Ródenas and Jorge Rodríguez, from the Barcelona Supercomputing Center is gratefully acknowledged. This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 667191. Mercè Planas-Fèlix is funded by the Obra Social Fundación la Caixa fellowship under the Severo Ochoa 2013 program. Work from Irene Miguel-Escalada, Ignasi Moran, Goutham Atla, and Jorge Ferrer was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, the Wellcome Trust (WT101033), Ministerio de Economía y Competitividad (BFU2014-54284-R) and Horizon 2020 (667191). Irene Miguel-Escalada has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska–Curie grant agreement No 658145. We acknowledge Prof. Giulio Cossu (Institute of Inflammation and Repair, University of Manchester) for providing the muscle myoblast cell line. We also acknowledge the InterAct and SIGMA Type 2 Diabetes Consortia for access to the data to replicate the rs146662075 variant. A full list of the investigators of the SIGMA Type 2 Diabetes and the InterAct consortia is provided in Supplementary Notes 3 and 4. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). This research has been conducted using the UK Biobank Resource (application number 16803). We also acknowledge Bianca C. Porneala, MS for his technical assistance in the collection and curation of the genotype and phenotype data from Partners Biobank. We also thank Marcin von Grotthuss for their support for uploading the summary statistics data to the Type 2 Diabetes Genetic Portal (AMP-T2D portal). Finally, we thank all the Computational Genomics group at the BSC for their helpful discussions and valuable comments on the manuscript. ; Peer Reviewed ; Postprint (published version)

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape. ; Funding: Funding for this study was provided by the Aarne Koskelo Foundation; the Aase and Ejner Danielsens Foundation; the Academy of Finland (40758, 41071, 77299, 102318, 104781, 117787, 117844, 118590, 120315, 121584, 123885, 124243, 124282, 126925, 129269, 129293, 129378, 130326, 134309, 134791, 136895, 139635, 211497, 263836, 263924, 1114194, 24300796); the Agency for Health Care Policy Research (HS06516); the Agency for Science, Technology and Research of Singapore (A*STAR); the Ahokas Foundation; the ALF/LUA research grant in Gothenburg; the ALK-Abello A/S (Horsholm, Denmark), Timber Merchant Vilhelm Bangs Foundation, MEKOS Laboratories Denmark; the Althingi (the Icelandic Parliament); the American Heart Association (AHA; 13POST16500011); the ANR ("Agence Nationale de la 359 Recherche"); the Ark (NHMRC Enabling Facility); the Arthritis Research UK (19542, 18030); the AstraZeneca; the Augustinus Foundation; the Australian National Health and Medical Research Council (NHMRC; 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506); the Australian Research Council (ARC; DP0770096 and DP1093502); the Becket Foundation; the bi-national BMBF/ANR funded project CARDomics (01KU0908A); the Biobanking and Biomolecular Resources Research Infrastructure (BBMRINL; 184.021.007, CP 32); the Biocentrum Helsinki; the Boehringer Ingelheim Foundation; the British Heart Foundation (RG/10/12/28456, SP/04/ 002); the Canadian Institutes for Health Reseaerch (FRCN-CCT-83028); the Cancer Research UK (C490/A10124, C490/A10119); the Center for Medical Systems Biology (CMSB; NWO Genomics); the Centers for Disease Control and Prevention and Association of Schools of Public Health (1734, S043, S3486); the Centre of Excellence Baden-Wurttemberg Metabolic Disorders; the Chief Scientist Office of the Scottish Government; the Clinical Research Facility at Guys & St Thomas NHS Foundation Trust; the Contrat de Projets Etat-Region (CPER); the Croatian Science Council (Grant no. 8875); the CVON (GENIUS); the Danish Agency for Science, Technology and Innovation; the Danish Centre for Health Technology Assessment, Novo Nordisk Inc.; the Danish Council for Independent Research (DFF 1333-00124); the Danish Diabetes Association; Danish Heart Foundation; the Danish Medical Research Council; the Danish Ministry of Internal Affairs and Health; the Danish National Research Foundation; the Danish Pharmaceutical Association; Danish Pharmacists Fund; the Danish Research Council; the Deutsche Forschungsgemeinschaft; the Diabetes Hilfs-und Forschungsfonds Deutschland (DHFD); the Dr. Robert Pfleger-Stiftung; the Dresden University of Technology Funding Grant, Med Drive; the Dutch Brain Foundation; the Dutch Diabetes Research Foundation; the Dutch Economic Structure Enhancing Fund (FES); the Dutch Kidney Foundation; the Dutch Ministry for Health, Welfare and Sports; the Dutch Ministry of Economic Affairs; the Dutch Ministry of Education, Culture and Science; the Egmont Foundation; the Else Kraner-Fresenius Stiftung (2012_A147, P48/08//A11/08); the Emil Aaltonen Foundation; the Erasmus Medical Center and Erasmus University, Rotterdam; the Estonian Ministry of Science and Education (SF0180142s08); the European Commission (223004, 2004310, DGXII, FP6-EUROSPAN, FP6-EXGENESIS, FP6-LSHG-CT2006-018947, FP6-LSHG-CT-2006-01947, FP6-LSHM- CT-2004-503485, FP6-LSHM-CT-2006037593, FP6-LSHM-CT-2007-037273, FP7-201379, FP7-201668, FP7-279143, FP7-305739, FP7313010, FP7-ENGAGE-HEALTH-F4-2007-201413, FP7-EurHEALTHAgeing-277849, FP7-HEALTH-F42007-201550, HEALTH-2011.2.4.2-2-EU-MASCARA, HEALTH-F2-2008-201865-GEFOS, HEALTH-F7305507 HOMAGE, LSHM-CT-2006-037593, QLG1CT-2001-01252, QLG1-CT-2002-00896, QLG2-CT2002-01254); the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO; the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN; 3.2.0304.11-0312); the European Research Council (ERC; 2011-StG-280559-SEPI, 2011-294713-EPLORE, 230374); the European Science Foundation (ESF; EU/QLRT-2001-01254); the EuroSTRESS project FP-006; the Finlands Slottery Machine Association; the Finnish Centre for Pensions (ETK); the Finnish Cultural Foundation; the Finnish Diabetes Association; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Foundation for Pediatric Research; the Finnish Funding Agency for Technology and Innovation (40058/07); the Finnish Medical Society; the Finnish Ministry of Education and Culture (627; 2004-2011); the Finnish Ministry of Health and Social Affairs (5254); the Finnish National Public Health Institute (current National Institute for Health and Welfare); the Finnish Special Governmental Subsidy for Health Sciences; the Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation; the Flemish League against Cancer, ITEA2 (project Care4Me); the Folkhalsan Research Foundation; the Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen; the Foundation for Life and Health in Finland; the Foundation for Strategic Research (SSF) and the Stockholm County Council (560283); the G. Ph. Verhagen Foundation; the Gene-diet Interactions in Obesity' project (GENDINOB); the Genetic Association Information Network (GAIN); the GENEVA Coordinating Center (U01 HG 004446); the GenomEUtwin (EU/QLRT2001-01254; QLG2-CT-2002-01254); the German Bundesministerium fuer Forschung und Technology (01 AK 803 A-H, 01 IG 07015 G); the German Diabetes Association; the German Ministry of Cultural Affairs; the German Federal Ministry of Education and Research (BMBF; 03IS2061A, 03ZIK012, 01ZZ9603, 01ZZ0103, 01ZZ0403); the German National Genome Research Network (NGFN-2 and NGFN-plus); the German Research Council (SFB1052 "Obesity mechanisms"); the Great Wine Estates of the Margaret River region of Western Australia; the Greek General Secretary of Research and Technology research grant (PENED 2003); the Gyllenberg Foundation; the Health Care Centers in Vasa, Narpes and Korsholm; the Health Fund of the Danish Health Insurance Societies; the Helmholtz Zentrum Munchen-German Research Center for Environmental Health; the Helsinki University Central Hospital special government funds (EVO #TYH7215, #TKK2012005, #TYH2012209); the Hjartavernd (the Icelandic Heart Association); the Ib Henriksen Foundation; the Illinois Department of Public Health, and the Translational Genomics Research Institute; the INTERREG IV Oberrhein Program (Project A28); the Interuniversity Cardiology Institute of the Netherlands (ICIN; 09.001); the Italian Ministry of Health "targeted project" (ICS110.1/RF97.71); the Italian National Centre of Research InterOmics PB05_ SP3; the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health; the Johns Hopkins University Center for Inherited Disease Research (CIDR); the Joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania; the Juho Vainio Foundation; the Juselius Foundation (Helsinki, Finland); the Juvenile Diabetes Research Foundation International (JDRF); the KfH Stiftung Praventivmedizin e. V.; the Knut and Alice Wallenberg Foundation; the Kuopio University Hospital; the Leenaards Foundation; the Leiden University Medical Center; the Liv och Halsa; the Local Government Pensions Institution (KEVA); the Lokaal Gezondheids Overleg (LOGO) Leuven and Hageland; the LudwigMaximilians- Universitat, as part of LMUinnovativ; the Lundberg Foundation; the March of Dimes Birth Defects Foundation; the Medical Research Council (G0601966; G0700931; G0000934; G0500539; G0600705; G1002319; G0701863; PrevMetSyn/SALVE; MC_ U106179471; MC_ UU_ 12019/1); the MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE); the MRC Centre for Obesity and Related Metabolic Diseases; the MRC Human Genetics Unit; the Medical Research Council of Canada; the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488); the Ministry of the Flemish Community, Brussels, Belgium (G. 0881.13 and G. 0880. 13); the MIUR-CNR Italian Flagship Project; the Montreal Heart Institute Foundation; the Munich Center of Health Sciences (MC Health); the Municipal Health Care Center and Hospital in Jakobstad; the Narpes Health Care Foundation; the National Alliance for Research on Schizophrenia and Depression (NARSAD); the National Cancer Institute (CA047988); the National Center for Advancing Translational Sciences (UL1TR000124); the National Center for Research Resources (U54RR020278); the National Heart, Lung and Blood Institute (NHLBI, 1RL1MH083268-01, 5R01HL087679-02, HHSN268200800007C, HHSN268201200036C, HL043851, HL080467, HL087647, HL36310, HL45670, N01HC25195, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N02HL64278, R01HL086694, R01HL087641, R01HL087652, R01HL087676, R01HL59367, R01HL103612, R01HL105756, R01HL120393, U01HL080295); the National Human Genome Research Institute (NHGRI, U01HG004402); the National Institute for Health and Welfare (THL); the National Institute for Health Research (NIHR, RP-PG-0407-10371); the National Institute of Allergy and Infectious Diseases (NIAID); the National Institute of Child Health and Human Development (NICHD); the National Institute of Diabetes and Digestive and Kidney Disease (NIDDKDRC, 1R01DK8925601, DK063491, R01DK089256, P30 DK072488); the National Institute of Food and Agriculture (2007-35205-17883); the National Institute of Neurological Disorders and Stroke (NINDS); the National Institute on Aging (NIA; 263-MA-410953, 263-MD-821336, 263-MD-9164, AG023629, AG13196, NO1AG12109, P30AG10161, R01AG15819, R01AG17917, R01AG023629, R01AG30146); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (5-P60-AR30701, 5-P60-AR49465-03); the National Institutes of Health (NIH; 1R01DK8925601, 1RC2MH089951, 1RC2MH089995, 1Z01HG000024, 2T32 HL 00705536, 5R01DK075681, 5R01MH63706: 02, AA014041, AA07535, AA10248, AA13320, AA13321, AA13326, AG028555, AG08724, AG04563, AG10175, AG08861, DA12854, DK046200, DK091718, F32AR059469, HG002651, HHSN268200625226C, HHSN268200782096C, HL084729, MH081802, N01AG12100, N01HG65403, R01AG011101, R01AG030146, R01D0042157-01A, R01DK062370, R01DK072193, R01DK093757, R01DK075787, R01DK075787, R01HL71981, R01MH59565, R01MH59566, R01MH59571, R01MH59586, R01MH59587, R01MH59588, R01MH60870, R01MH60879, R01MH61675, R01MH67257, R01MH81800, R01NS45012, U01066134, U01CA098233, U01DK062418, U01GM074518, U01HG004423, U01HG004436, U01HG004438, U01HL072515-06, U01HL105198, U01HL84756, U01MH79469, U01MH79470, U01NS069208-01, UL1RR025005); the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; the NIHR Cambridge Biomedical research Centre; the Netherlands Heart Foundation (2001 D 032); the Netherlands Organisation for Scientific Research (NWO; Geestkracht program grant 10-000-1002; 050-060-810; 100-001-004; 175.010.2003.005; 175.010.2005.011; 175.010.2007. 006; 261-98-710; 40-0056-98-9032; 400-05-717; 452-04-314; 452-06-004; 480-01-006; 480-04-004; 480-05-003; 480-07-001; 481-08-013; 60-60600-97-118; 904-61-090; 904-61-193; 911-03012; 985-10-002; Addiction-31160008; GB-MW 94038- 011; SPI 56-464-14192); the Netherlands Organization for the Health Research and Development (ZonMw; 91111025); the Nordic Center of Excellence in Disease Genetics; the Nordic Centre of Excellence on Systems biology in controlled dietary interventions and cohort studies, SYSDIET (070014); the Northern Netherlands Collaboration of Provinces (SNN); the Novo Nordisk Foundation; the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; the Ollqvist Foundation; the Paavo Nurmi Foundation; the Pahlssons Foundation; the Paivikki and Sakari Sohlberg Foundation; the Perklen Foundation; the Republic of Croatia Ministry of Science, Education and Sports research (108-1080315-0302); the Research Centre for Prevention and Health, the Capital Region of Denmark; the Research Foundation of Copenhagen County; the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the Reynold's Foundation; the Rotterdam Oncologic Thoracic Study Group, Erasmus Trust Fund, Foundation against Cancer; the Royal Swedish Academy of Science; the Russian Foundation for Basic Research (NWO-RFBR 047.017.043); the Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); the Samfundet Folkhalsan; the Sigrid Juselius Foundation; the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (9M048, 9N035); the Social Ministry of the Federal State of Mecklenburg-West Pomerania; the Societe Francophone du 358 Diabste (SFD); the South Tyrolean Sparkasse Foundation; the Stichting Nationale Computerfaciliteiten (National Computing Facilities Foundation, NCF); the Strategic Cardiovascular Programme of Karolinska Institutet and the Stockholm County Council (560183); the Susan G. Komen Breast Cancer Foundation; the Swedish Cancer Society; the Swedish Cultural Foundation in Finland; the Swedish Diabetes Association; the Swedish Diabetes Foundation (grant no. 2013-024); the Swedish Foundation for Strategic Research (SSF; ICA08-0047); the Swedish HeartLung Foundation (20120197); the Swedish Medical Research Council (K2007-66X-20270-01-3, 20121397); the Swedish Ministry for Higher Education; the Swedish Research Council (8691, M-2005-1112, 2009-2298); the Swedish Society for Medical Research; the Swiss National Science Foundation (31003A-143914, 3200B0105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30148401); SystemsX. ch (51RTP0_151019); the Tampere Tuberculosis Foundation; the TEKES (70103/06, 40058/07); the The Paul Michael Donovan Charitable Foundation; the Torsten and Ragnar Sderberg Foundation; the Umea Medical Research Foundation; the United Kingdom NIHR Cambridge Biomedical Research Centre; the Universities and Research of the Autonomous Province of Bolzano, South Tyrol; the University Hospital of Regensburg (ReForM A, ReForM C); the University Hospital Oulu, Biocenter, University of Oulu, Finland (75617); the University Medical Center Groningen; the University of Groningen; the University of Maryland General Clinical Research Center (M01RR16500, AG000219); the University of Tartu (SP1GVARENG); the University of Tromso, Norwegian Research Council (185764); the Vasterbottens Intervention Programme; the Velux Foundation; the VU University Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the Wellcome Trust (064890, 068545/Z/02, 076113/B/04/Z, 077016/Z/05/Z, 079895, 084723/Z/08/Z, 086596/Z/ 08/Z, 088869/B/09/Z, 089062, 090532, 098017, 098051, 098381); the Western Australian DNA Bank (NHMRC Enabling Facility); the Yrjo Jahnsson Foundation (56358); and the Zorg Onderzoek Nederland-Medische Wetenschappen, KWF Kankerbestrijding, Stichting Centraal Fonds Reserves van voormalig Vrijwillige Ziekenfondsverzekeringen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. More details of acknowledgements can be found in S2 Text.