We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10−20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10−13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10−10) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data. ; We acknowledge The Cancer Genome Atlas (TCGA) for their contribution of lung cancer genomic data to this study (TCGA Project Number 3230). We also acknowledge support from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. This study was supported by the NIH (U19CA148127, R01CA055769, 5R01CA127219, 5R01CA133996 and 5R01CA121197). The work performed at ICR was supported by Cancer Research UK (C1298/A8780 and C1298/A8362), National Cancer Research Network (NCRN), HEAL, Sanofi-Aventis and National Health Service funding to the Royal Marsden Hospital and Institute of Cancer Research, as well as the National Institute for Health Research Biomedical Research Centre. B.K. was the recipient of a Sir John Fisher Foundation PhD studentship. Work at ICR was also supported by NIH GM103534 and the Institute for Quantitative Biomedical Sciences at Dartmouth to C.I.A. The work performed in Toronto was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The work performed at Heidelberg was supported by Deutsche Krebshilfe (70-2387 and 70-2919) and the German Federal Ministry of Education and Research (EPIC-Heidelberg). The work performed at IARC was supported by the Institut National du Cancer, France, the European Community (LSHG-CT-2005-512113), the Norwegian Cancer Association, the Functional Genomics Programme of Research Council of Norway, the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), the NIH (R01-CA111703 and UO1-CA63673), the Fred Hutchinson Cancer Research Center, the US NCI (R01 CA092039), an FP7 grant (REGPOT 245536), the Estonian Government (SF0180142s08), the EU European Regional Development Fund in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure's Roadmap and the University of Tartu (SP1GVARENG) and an IARC Postdoctoral Fellowship (M.N.T.). Work at the NCI was supported by the Intramural Research Program of the NIH, the NCI, US Public Health Service contracts NCI (N01-CN-45165, N01-RC-45035, N01-RC-37004, NO1-CN-25514, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476 and NO1-CN-25404), the American Cancer Society, the NIH Genes, Environment and Health Initiative in part by HG-06-033-NCI-01 and RO1HL091172-01, genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446). Work was also supported by NIH grants (P50 CA70907, R01CA121197, RO1 CA127219, U19 CA148127 and RO1 CA55769) and a Cancer Prevention Research Institute of Texas grant (RP100443). Genotyping was provided by the Center for Inherited Disease Research (CIDR). Work performed at Harvard was supported by the NIH (CA074386, CA092824 and CA090578). The Icelandic study was supported in part by NIH DA17932.
Altres ajuts: The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. ; Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10 −15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10 −9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10 −8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L - TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 ...
In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene. ; This work was supported by RO1 CA154823, the Lustgarten Foundation, and federal funds from the NCI, US NIH under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, and mention of trade names, commercial products, or organizations does not imply endorsement by the US government. Geno-typing Services were provided by the CIDR and the NCIs CGR. CIDR is fully funded through a federal contract from the NIH to the Johns Hopkins University, contract number HHSN268201100011I. The IARC/Central Europe study was supported by a grant from the US NCI at the NIH (R03 CA123546-02) and grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3, and MH CZ- DRO-MMCI 00209805). The work at Johns Hopkins University was supported by the NCI Grants P50CA062924 and R01CA97075. Additional support was provided by, Susan Wojcicki, and Dennis Troper, and the Sol Goldman Pancreas Cancer Research Center. The Mayo Clinic Biospecimen Resource for Pancreas Research study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). The Memorial Sloan Ket- tering Cancer Center Pancreatic Tumor Registry is supported by P30CA008748, the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family, Foundation, and the Society of MSKCC. The PACIFIC Study was supported by RO1CA102765, Kaiser Permanente, and Group Health Cooperative. The Queensland Pancreatic Cancer Study was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC; Grant number 442302). R.E.N. is supported by a NHMRC Senior Research Fellowship (#1060183). The UCSF pancreas study was supported by NIH-NCI grants (R01CA1009767, R01CA109767-S1, and R0CA059706) and the Joan Rombauer Pancreatic Cancer Fund. Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting pro- gram; the NCIs SEER Program under contract HSN261201000140C awarded to CPIC; and the CDCs National Program of Cancer Registries, under agreement #U58DP003862-01 awarded to the California Department of Public Health. The Yale (CT) pancreas cancer study is supported by NCI at the U.S. NIH, grant 5R01CA098870. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access is gratefully acknowledged. The Connecticut Pancreas Cancer Study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in that study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data. Studies included in PAN- DoRA were partly funded by the Czech Science Foundation (No. P301/12/1734), the Internal Grant Agency of the Czech Ministry of Health (IGA NT 13 263); the Baden- Württemberg State Ministry of Research, Science and Arts (Professor H. Brenner), the Heidelberger EPZ-Pancobank (Professor M.W. Büchler and team: Professor T. Hackert, Dr. N. A. Giese, Dr. Ch. Tjaden, E. Soyka, M. Meinhardt; Heidelberger. Stiftung Chir- urgie and BMBF grant 01GS08114), the BMBH (Professor P. Schirmacher; BMBF grant 01EY1101), the " 5 × 1000 " voluntary contribution of the Italian Government, the Italian Ministry of Health (RC1203GA57, RC1303GA53, RC1303GA54, and RC1303GA50), the Italian Association for Research on Cancer (Professor A. Scarpa; AIRC n. 12182), the Italian Ministry of Research (Professor A. Scarpa; FIRB - RBAP10AHJB), the Italian FIMP-Ministry of Health (Professor A. Scarpa; 12 CUP_J33G13000210001), and by the National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, UK. We would like to acknowledge the contribution of Dr. Frederike Dijk and Professor Oliver Busch (Academic Medical Center, Amsterdam, the Netherlands). Assistance with genotype data quality control was provided by Cecelia Laurie and Cathy Laurie at the University of Washington Genetic Analysis Center. The American Cancer Society (ACS) funds the creation, maintenance, and updating of the Cancer Prevention Study II cohort. Cancer incidence data for CLUE were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene, 201 W. Preston Street, Room 400, Baltimore, MD 21201, http://phpa.dhmh.maryland.gov/ cancer , 410-767-4055. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data. We thank all the CLUE participants. The Melbourne Col- laborative Cohort Study (MCCS) recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414 and by the infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The NYU study (AZJ and AAA) was funded by NIH R01 CA098661, UM1 CA182934 and center grants P30 CA016087 and P30 ES000260. The PANKRAS II Study in Spain was supported by research grants from Instituto de Salud Carlos III-FEDER, Spain: Fondo de Investigaciones Sanitarias (FIS; #PI13/00082 and #PI15/01573) and Red Temática de Investigación Cooperativa en Cáncer, Spain (#RD12/ 0036/0050); and European Cooperation in Science and Technology (COST Action #BM1204: EU_Pancreas), Ministerio de Ciencia y Tecnología (CICYT SAF 2000-0097), Fondo de Investigación Sanitaria (95/0017), Madrid, Spain; Generalitat de Catalunya(CIRIT—SGR);"Red temática de investigación cooperativa de centros en Cáncer (C03/10),"Red temática de investigación cooperativa de centros en Epidemiología y salud pública(C03/09), and CIBER de Epidemiología (CIBERESP), Madrid. The Physicians 'Health Study was supported by research grants CA-097193, CA-34944, CA-40360, HL- 26490, and HL-34595 from the NIH, Bethesda, MD, USA. The Womens Health Study was supported by research grants CA-047988, HL-043851, HL-080467, and HL-099355 from the NIH, Bethesda, MD, USA. Health Professionals Follow-up Study is supported by NIH grant UM1 CA167552 from the NCI, Bethesda, MD, USA. Nurses ' Health Study is supported by NIH grants UM1 CA186107, P01 CA87969, and R01 CA49449 from the NCI, Bethesda, MD, USA. Additional support from the Hale Center for Pancreatic Cancer Research, U01 CA21017 from the NCI, Bethesda, MD, USA, and the United States Department of Defense CA130288, Lustgarten Foundation, Pancreatic Cancer Action Network, Noble Effort Fund, Peter R. Leavitt Family Fund, Wexler Family Fund, and Promises for Purple to B.M. Wolpin is acknowledged. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf . We thank Laurie Burdett, Aurelie Vogt, BelyndaHicks, Amy Hutchinson, Meredith Yeager, and other staff at the NCI's Division ofEpidemiology and Genetics (DECG) CGR for GWAS genotyping. We also thank Bao Tran, Jyoti Shetty, and other members of the NCI Center for Cancer Research (CCR) Sequencing Facility for sequencing RNA from histologically normal pancreatic tissue samples (LTG samples). This study utilized the high-performance computational cap- abilities of the Biowulf Linux cluster at the NIH, Bethesda, MD, USA (http://biowulf.nih.gov). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the pancreatic tissue data from the GTEx Portal on 05/04/17. The results published here are in part based upon data generated by The Cancer Genome Atlas (TCGA) managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov/. We acknowledge the clinical contributors that provided PDAC samples and the data producers of RNA-seq and GWAS genotype data from TCGA Research Network. The data set used for the analyses described in this manuscript was obtained by formal permission through the TCGA Data Access Committee (DAC) ; Sí
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.