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Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Nature Genetics volume 47, pages 12821293 (2015) | Download Citation

Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

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Acknowledgements

We acknowledge the use of data from the International Consortium for Blood Pressure Genome-Wide Association Studies8,9.

AASC.This work was supported by Grants for Scientific Research (24390084, 21390099 and 20390185) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; a Science and Technology Incubation Program in Advanced Regions, Japanese Science and Technology Agency; the Japanese Atherosclerosis Prevention Fund; the Takeda Medical Research Foundation; and National Cardiovascular Research Grants.

AIDHS/SDS. This study was supported by US National Institutes of Health (NIH) grants R01DK082766 (D.K.S.) funded by the National Institute of Diabetes and Digestive and Kidney Diseases and NOT-HG-11-009 (D.K.S.) funded by the National Human Genome Research Institute (D.K.S.) and by a VPR bridge grant (D.K.S.) from the University of Oklahoma Health Sciences Center.

BIOS-consortium. The BIOS-consortium is funded by BBMRI-NL, a research infrastructure financed by the Netherlands Organization for Scientific Research (NWO project 184.021.007).

CAGE-Amagasaki. We acknowledge the outstanding contributions of the employees of the National Center for Global Health and Medicine who provided technical and infrastructural support for this work. Above all, we thank the participants who made this work possible and who gave it value. We also thank T. Ogihara, Y. Yamori, A. Fujioka, C. Makibayashi, S. Katsuya, K. Sugimoto, K. Kamide, R. Morishita and the many physicians of the participating hospitals and medical institutions in the Amagasaki Medical Association for their assistance in collecting the DNA samples and accompanying clinical information. This work was supported by Grants for Scientific Research (22390186, 24591060, 25253059 and 25461127) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

CAGE-Fukuoka. This work was supported by Grants-in-Aid for the 21st Century Center of Excellence Program (Kyushu University) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grants-in-Aid for Scientific Research (category A) from the Japanese Society for the Promotion of Science. We are grateful to all participants of this study. We also especially thank S. Kono for his management of the DNA samples and clinical information.

CAGE_GWAS1. The CAGE Network studies were supported by grants for Core Research for Evolutional Science and Technology (CREST) from the Japanese Science and Technology Agency; the Program for the Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); KAKENHI (Grant-in-Aid for Scientific Research) on Priority Area 'Applied Genomics' from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and a grant from the National Center for Global Health and Medicine. N.K. is a recipient of the Okinaga Scholarship and thanks S. Okinaga, H. Okinaga and other staff at Teikyo University, Japan, for their considerable support of doctoral work.

CAGE-KING. This study was supported in part by Grants-in-Aid for Scientific Research, including ones from categories A and B and the NEXT program of the Japanese Society for the Promotion of Science and by Grants-in-Aid on Priority Areas 'Comprehensive Genomics' and 'Applied Genomics', from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

CAGE-Vietnam. The CAGE-Vietnam study was supported by Grants for International Health Research (17C-1 and 20S-6) from the Ministry of Health, Labour and Welfare of Japan, grants for the National Center for Global Health and Medicine (22S-10 and 25S-1) and the Manpei Suzuki Diabetes Foundation. We acknowledge the following investigators and institutions for their substantial contribution to the current study: T. Sasazuki, M. Noda, N. Kato, S. Kanagawa, T. Mizoue, H. Ohara and Y. Takahashi (Japanese investigators); T. Quy, N. Lan Viet, P. Thi Hong Hoa, N. Hoa Dieu Van, N. Thi Lam, L. Bach Mai, N. Quang Bay, P. Thi Phuong Thuy and B. Minh Duc (Vietnamese investigators); the National Center for Global Health and Medicine (Japan), Bach Mai Hospital (Vietnam), the Vietnam National Institute of Nutrition and the NCGM-BMH Medical Collaboration Center.

Cilento. We thank the populations of Cilento, Italy, for their participation in the study. This work was supported by grants from the Italian Ministry of Universities (FIRB-RBNE08NKH7, Interomics Flag project), the Assessorato Ricerca Regione Campania, the Fondazione con il SUD (2011-PDR-13) and the Fondazione Banco di Napoli to M.C.

CLHNS. We thank the Office of Population Studies Foundation research and data collection teams for the Cebu Longitudinal Health and Nutrition Survey. This work was supported by National Institutes of Health grants DK078150, TW05596, HL085144 and TW008288 and pilot funds from RR20649, ES10126 and DK56350.

DIABNORD. We are grateful to the study participants who dedicated their time and samples to these studies. We also thank the VHS, the Swedish Diabetes Registry and the Umeå Medical Biobank staff for biomedical data and DNA extraction. We also thank M. Sterner, M. Juhas and P. Storm for their expert technical assistance with genotyping and genotype data preparation. The current study was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation and the Skåne Regional Health Authority (all to P.W.F.).

EGCUT. EGCUT received targeted financing from the Estonian government (SF0180142s08), the Center of Excellence in Genomics (EXCEGEN) and the University of Tartu (SP1GVARENG). We acknowledge EGCUT technical personnel, especially V. Soo and S. Smit. Data analyses were carried out in part at the High-Performance Computing Center of the University of Tartu.

FINCAVAS. This work was supported by Competitive Research Funding from Tampere University Hospital (grants 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, and the Tampere Tuberculosis Foundation. The authors thank the staff of the Department of Clinical Physiology for collecting the exercise test data.

GEMS. This work was partially supported by US NIH grants R01CA107431 and P42ES10349 to H. Ahsan. We would like to thank the study participants, as well as the staff of UChicago Research Bangladesh.

GeneBank. The Cleveland Clinic GeneBank study is supported by National Heart, Lung, and Blood Institute grants P01HL098055, P01HL076491, R01HL103866, P20HL113452 and R01HL103931. H. Allayee was supported by grant R01ES021801 from the National Institute of Environmental Health Sciences.

GenSalt. The Genetic Epidemiology Network of Salt Sensitivity is supported by research grants (U01HL072507, R01HL087263 and R01HL090682) from the National Heart, Lung, and Blood Institute, US NIH.

GLACIER-exome. We are indebted to the study participants who dedicated their time and samples to these studies. We thank J. Hutiainen and Å. Ågren (Umeå Medical Biobank) for data organization and K. Enquist and T. Johansson (Västerbottens County Council) for technical assistance with DNA extraction. We also thank M. Sterner, M. Juhas and P. Storm for their expert technical assistance with genotyping and genotype data preparation. The current study was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation and the Skåne Regional Health Authority (all to P.W.F.).

GLACIER Metabochip. We are indebted to the study participants who dedicated their time and samples to these studies. We also thank the VIP and Umeå Medical Biobank staff for biomedical data collection and preparation. We specifically thank J. Hutiainen, Å. Ågren and S. Nilsson (Umeå Medical Biobank) for data organization, K. Enquist and T. Johansson (Västerbottens County Council) for expert technical assistance with DNA preparation, and D. Hunter, P. Soule and H. Ranu (Harvard School of Public Health) for expert assistance with planning and undertaking genotyping of GLACIER samples. The current study was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation and the Skåne Regional Health Authority (all to P.W.F.).

Health2006. The Health2006 study was financially supported by grants from the Velux Foundation; the Danish Medical Research Council, Danish Agency for Science, Technology and Innovation; the Aase and Ejner Danielsens Foundation; and ALK-Abello (Hørsholm, Denmark), Timber Merchant Vilhelm Bangs Foundation, MEKOS Laboratories Denmark and Research Centre for Prevention and Health, the Capital Region of Denmark. This project was also funded by the Lundbeck Foundation and produced by the Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp; http://www.lucamp.org/). The Novo Nordisk Foundation Centre for Basic Metabolic Research is an independent Research Centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk/).

HEXA. This work was supported by grants from the Korean Centers for Disease Control and Prevention (4845-301, 4851-302 and 4851-307) and an intramural grant from the Korean National Institute of Health (2012-N73002-00), Republic of Korea.

HPS. The Heart Protection Study (ISRCTN48489393) was funded by the UK Medical Research Council, the British Heart Foundation, Merck & Co., and Roche Vitamins, Ltd. Genotyping and analysis were supported by a grant to the University of Oxford and the Centre National de Génotypage from Merck & Co. and the Oxford British Heart Foundation Centre of Research Excellence. J.C.H. acknowledges support from the British Heart Foundation (FS/14/55/30806).

GOYA. This study was conducted as part of the activities of the Gene-Diet Interactions in Obesity project (GENDINOB; http://www.gendinob.dk/) and the Medical Research Council Centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). We thank the staff of the Copenhagen City Heart Study for their skillful examination of the study subjects in the collection of baseline and follow-up data. T.S.A. was also funded by the GENDINOB project and acknowledges the same.

GUSTO. The GUSTO study group includes P. Agarwal, A. Biswas, C. Looi Bong, B.F.P. Broekman, S. Cai, J.K.Y. Chan, Y.H. Chan, C.Y.I. Chee, H.Y.H. Chen, Y.B. Cheung, A. Chia, A. Chinnadurai, C.K. Chng, M.F.-F. Chong, S.C. Chong, M.C. Chua, C.M. Ding, E.A. Finkelstein, D. Fok, M. Fortier, A.E.N. Goh, Y.T.D. Goh, J.J. Gooley, W.M. Han, M. Hanson, C.J. Henry, C.-Y. Hsu, H. Inskip, J. Kapur, K. Kwek, I.Y.-M. Lau, B.W. Lee, N. Lek, S.B. Lim, Y.-L. Low, I. Magiati, L. Mary Daniel, C. Ngo, K. Naiduvaje, W.W. Pang, A. Qiu, B.L. Quah, V.S. Rajadurai, M. Rauff, S.A. Rebello, J.L. Richmond, A. Rifkin-Graboi, L.P.-C. Shek, A. Sheppard, B. Shuter, L. Singh, W. Stunkel, L.L. Su, O.H. Teoh, H.P.S. van Bever, R.M. van Dam, I.B.Y. Wong, P.C. Wong and G.S.H. Yeo. This research is supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore-NMRC/TCR/012-NUHS/2014. Additional funding is provided by the Singapore Institute for Clinical Sciences, A*STAR, Singapore.

INGI-VB. The research was supported by funds from Compagnia di San Paolo (Torino, Italy); Fondazione Cariplo, Italy, and the Ministry of Health, Ricerca Finalizzata 2008 and CCM 2010, and Telethon, Italy, to D.T. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank the inhabitants of Val Borbera who made this study possible, the local administrations, the Tortona and Genova archdioceses, and the ASL-22, Novi Ligure (Al), for support. We also thank C. Camaschella for the supervision of data collection and organization of the clinical data collection, F. Viganò for technical help, and C. Masciullo and M. Cocca for building the analysis platform.

Inter99. Inter99 was initiated by T.J. (principal investigator), K. Borch-Johnsen (co-principal investigator), H. Ibsen and T.F. Thomsen. The steering committee comprises the first two and C. Pisinger. The study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk, the Research Foundation of Copenhagen County, the Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation and the Danish Diabetes Association. This project was also funded by the Lundbeck Foundation and produced by LuCamp (http://www.lucamp.org/). The Novo Nordisk Foundation Centre for Basic Metabolic Research is an independent Research Centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk/).

InterAct. We are grateful to all participants who gave their time and effort to the study. We are also extremely grateful to all persons who contributed to the data collection across the study sites. This study was supported by funding from the European Union (integrated project LSHM-CT-2006-037197 in the Sixth Framework Programme of the European Community) and the Medical Research Council, UK.

JMGP. The JMGP study group is composed of the following individuals; JMGP-Ohasama: T. Ohkubo, M. Satoh, R. Inoue, T. Hirose, H. Metoki, M. Kikuya and Y. Imai; JMGP-Yokohama: N. Hirawa, K. Yatsu, T. Shiwa, M. Ogawa and S. Umemura; JMGP-Shigaraki and Takashima: Y. Kita, Y. Nakamura, N. Takashima and H. Ueshima; and JMGP-Nomura: Y. Tabara, R. Kawamoto, K. Kohara and T. Miki (chairperson).

This work was supported by Grants-in-Aid for Scientific Research (Priority Areas 'Medical Genome Science (Millennium Genome Project)' and 'Applied Genomics'), the Leading Project for Personalized Medicine and Scientific Research (20390185, 21390099, 19659163, 16790336, 12204008, 15790293, 16590433, 17790381, 17790381, 18390192, 18590265, 18590587, 18590811, 19590929, 19650188, 19790423, 17390186, 20390184 and 21390223) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grants-in-Aid (H15-Longevity-005, H17-Longevity-003, H16-Kenko-001, H18-Longevity (kokusai), H11-Longevity-020, H17-Kenkou-007, H17-Pharmaco-common-003, H18-Junkankitou[Seishuu]-Ippan-012 and H20-Junkankitou[Seishuu]-Ippan-009, 013) from the Ministry of Health, Labor and Welfare of Japan, Health and Labor Sciences Research Grants, Japan; a Science and Technology Incubation Program in Advanced Regions, the Japanese Science and Technology Agency; Grants-in-Aid from Japanese Society for the Promotion of Science fellows (16.54041, 18.54042, 19.7152, 20.7198, 20.7477 and 20.54043); Health Science Research Grants and Medical Technology Evaluation Research Grants from the Ministry of Health, Labour and Welfare of Japan; the Japanese Atherosclerosis Prevention Fund; the Uehara Memorial Foundation; the Takeda Medical Research Foundation; National Cardiovascular Research Grants; Biomedical Innovation Grants; and the Japanese Research Foundation for Clinical Pharmacology.

KARE. This work was supported by grants from the Korean Centers for Disease Control and Prevention (4845-301, 4851-302 and 4851-307) and an intramural grant from the Korean National Institute of Health (2012-N73002-00), Republic of Korea.

KORA. KORA was initiated and financed by the Helmholtz Zentrum München–German Research Center for Environmental Health and supported by grants from the German Federal Ministry of Education and Research (BMBF), the Federal Ministry of Health and the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. This research was supported by a grant from the German-Israeli Foundation for Scientific Research and Development, by the European Union's Seventh Framework Programme (FP7-HEALTH-F5-2012) under grant agreement 305280 (MIMOmics), by Helmholtz-Russia Joint Research Group (HRJRG) 310 and by the German Center for Diabetes Research (DZD). We thank all members of the field staff who were involved in the planning and conduct of the MONICA/KORA Augsburg studies. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. C.G. is supported by EU-FP7-HEALTH grant 602936: CARTARDIS–Identification and Validation of Novel Pharmaceutical Drug Targets for Cardiovascular Disease and BMBF e:Med project e:AtheroSysMed–Systems Medicine of Myocardial Infarction and Stroke.

LBC1921. We thank the cohort participants and team members who contributed to these studies. Phenotype collection was supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC), the Royal Society and the Chief Scientist Office of the Scottish government. Genotyping was funded by the BBSRC. The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council, UK, is gratefully acknowledged.

LBC1936. We thank the cohort participants and team members who contributed to these studies. Phenotype collection was supported by Age UK (The Disconnected Mind project). Genotyping was funded by the BBSRC. The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council, UK, is gratefully acknowledged.

LifeLines. The LifeLines Cohort Study and the generation and management of GWAS genotype data for the LifeLines Cohort Study are supported by the Netherlands Organization for Scientific Research (NWO; grant 175.010.2007.006), the Economic Structure-Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the province of Groningen, University Medical Center Groningen, the University of Groningen, the Dutch Kidney Foundation and the Dutch Diabetes Research Foundation. We thank B. Alizadeh, A. Boesjes, M. Bruinenberg, N. Festen, I. Nolte, L. Franke and M. Valimohammadi for their help in creating the GWAS database and R. Bieringa, J. Keers, R. Oostergo, R. Visser and J. Vonk for their work related to data collection and validation. The authors are grateful to the study participants, the staff of the LifeLines Cohort Study and Medical Biobank Northern Netherlands, and the participating general practitioners and pharmacists. LifeLines Scientific Protocol Preparation: R. de Boer, H. Hillege, M. van der Klauw, G. Navis, H. Ormel, D. Postma, J. Rosmalen, J. Slaets, R. Stolk and B. Wolffenbuttel; LifeLines GWAS Working Group: B. Alizadeh, M. Boezen, M. Bruinenberg, N. Festen, L. Franke, P. van der Harst, G. Navis, D. Postma, H. Snieder, C. Wijmenga and B. Wolffenbuttel.

LOLIPOP. The LOLIPOP study is supported by the NIHR Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council, UK (G0601966 and G0700931), the Wellcome Trust (084723/Z/08/Z), the NIHR (RP-PG-0407-10371), the European Union's Seventh Framework Programme (EpiMigrant, 279143) and Action on Hearing Loss (G51). We thank the participants and research staff who made the study possible.

LURIC. We extend our appreciation to the participants of the LURIC study; without their collaboration, this report would not have been written. We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital, the University of Freiburg and the University of Ulm, Germany. LURIC has received funding from the Sixth Framework Programme (integrated project Bloodomics, grant LSHM-CT-2004-503485) and from the Seventh Framework Programme (Atheroremo, grant agreement 201668 and RiskyCAD, grant agreement 305739) of the European Union as well as from the INTERREG IV Oberrhein Program (project A28, Genetic Mechanisms of Cardiovascular Diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO.

NFBC86. We thank P. Rantakallio (launch of NFBC1986 and initial data collection), S. Vaara (data collection), T. Ylitalo (administration), M. Koiranen (data management), and O. Tornwall and M. Jussila (DNA biobanking). Financial support was provided by the Academy of Finland (project grants 104781, 120315, 129269 Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Fifth Framework Programme award QLG1-CT-2000-01643), National Heart, Lung, and Blood Institute grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), the US NIH/National Institute of Mental Health (5R01MH63706:02), the ENGAGE project and grant agreement HEALTH-F4-2007-201413 and the Medical Research Council, UK (grants G0500539, G0600331 nad PrevMetSyn). DNA extraction, sample quality control, biobank upkeep and aliquotting were performed at the National Public Health Institute, Biomedicum Helsinki, Finland, and supported financially by the Academy of Finland and Biocentrum Helsinki. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

NHAPC. The authors thank all of the participants in this study. The authors also thank the Bio-X Institute, Shanghai Jiao Tong University and the Chinese National Human Genome Center in Shanghai for performing DNA microarray analysis.

POPGEN. The POPGEN study was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN) and the Ministry of Science, Commerce and Transportation of the state of Schleswig-Holstein. The project has also received infrastructure support through the DFG excellence cluster 'Inflammation at Interfaces'. The POPGEN 2.0 network is supported by a grant from the German Ministry of Education and Research (01EY1103).

PREVEND. PREVEND genetics is supported by the Dutch Kidney Foundation (grant E033), European Union project grant GENECURE (FP-6 LSHM CT 2006 037697), the US NIH (grant 2R01LM010098), the Netherlands Organization for Health Research and Development (NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70 and ZonMw grant 90.700.441) and the Dutch Interuniversity Cardiology Institute Netherlands (ICIN).

PROMIS. Genotyping in PROMIS was supported by the Wellcome Trust and Pfizer. Some core support to PROMIS was provided by the British Heart Foundation. The Cardiovascular Epidemiology Unit at the University of Cambridge is underpinned by the Medical Research Council, UK (G0800270), the British Heart Foundation (SP/09/002), the British Heart Foundation Cambridge Cardiovascular Centre of Excellence and the NIHR Cambridge Biomedical Research Centre.

PROSPER. 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). Support for genotyping was provided 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).

RHS. RHS was supported by a grant from the National Center for Global Health and Medicine.

Rotterdam Study. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of the Illumina 450K methylation array data (EWAS data) for the Rotterdam Study were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center, the Netherlands. The EWAS data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center, and by the Netherlands Organization for Scientific Research (NWO; project 184021007) and were made available as a Rainbow Project (RP3; BIOS) of BBMRI-NL. We thank M. Verbiest, M. Jhamai, S. Higgins and M. Verkerk for their help in creating the methylation database.

SCES. SCES is funded by the Biomedical Research Council of Singapore (grant 08/1/35/19/550) and the NMRC, Singapore (grants STaR/0003/2008 and CG/SERI/2010). The National University Health System Tissue Repository and the Genome Institute of Singapore (A*STAR, Singapore) provided services for tissue archiving and genotyping, respectively.

SCHS. We would like to thank S.-H. Low of the National University of Singapore for supervising the field work of the Singapore Chinese Health Study and K. Arakawa for development of the cohort study database. The founding, long-standing principal investigator of the Singapore Chinese Health Study is M.C. Yu. Significant contributions to the GWAS substudy of SCHS were made by W.-P. Koh, J.-M. Yuan, R. Wang, Z. Chen, M. Seielstad, A.O. Odegaard, E.S. Tai, Y.-Y. Teo, J. Liu, B. Thyagarajan and R. Koratkar. Funding sources included Genetic and Environmental Determinants of Type 2 Diabetes in Chinese Singaporeans, grant R01DK080720 from the US NIH. Additional support came from the NMRC of Singapore under the individual research grants scheme, from the Genome Institute of Singapore, the NMRC of Singapore under its individual research grants and clinician scientist award scheme, and from A*STAR, Singapore. The Singapore Chinese Health Study primary cohort was supported by US NIH/National Cancer Institute grants RO1CA55069, R35CA53890, R01CA80205 and R01CA144034.

SCHS_MI. SCHS was supported by the US NIH (NCI RO1CA55069, R35CA53890, R01CA80205 and R01CA144034), the NUS-HUJ CREATE Programme of the National Research Foundation, Singapore (project 370062002) and a grant from the NMRC, Singapore (NMRC/1270/2010).

SiMES. SiMES is funded by the NMRC, Singapore (grants 0796/2003, IRG07nov013, IRG09nov014, STaR/0003/2008 and CG/SERI/2010) and the Biomedical Research Council of Singapore (grant 09/1/35/19/616). The Singapore Tissue Network and the Genome Institute of Singapore (A*STAR, Singapore) provided services for tissue archiving and genotyping, respectively.

SINDI. SINDI is funded by the Biomedical Research Council of Singapore (grant 08/1/35/19/550) and the NMRC, Singapore (grants STaR/0003/2008 and CG/SERI/2010). The National University Health System Tissue Repository and the Genome Institute of Singapore (A*STAR, Singapore) provided services for tissue archiving and genotyping, respectively.

SMART. This research was financially supported by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007).

SMHS. The study was supported by grants RO1CA82729 and UM1CA173640 from the US NIH. The authors thank the participants and staff members of the SMHS research team for their important contributions.

SMSS. SMSS was supported by the National Natural Science Foundation of China (grant 81172761) and the Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions.

SP2. This project acknowledges the support of the Yong Loo Lin School of Medicine, the National University Health System and the Life Sciences Institute of the National University of Singapore. We also acknowledge the support of the National Research Foundation of Singapore (NRF-RF-2010-05), the Biomedical Research Council of Singapore (under the individual research grants scheme) and the NMRC, Singapore, under the individual research grant and the clinician scientist award schemes).

SRS. This work was supported by the Chinese National Key Program for Basic Research (973 grants: 2004CB518603, 2006CB503804 and 2009CB521905), the Chinese National High-Tech Program (863 grants: 2009AA022703 and 2006AA022179) and the Ministry of Science and Technology, National Natural Science Foundation of China (30871361).

SWHS. This research was supported by US NIH research grant R37CA70867. The authors thank the participants and staff members of SWHS for their important contributions.

TWSC. We gratefully acknowledge the members of the Translational Resource Center (TRC) (NSC102-2325-B-001-040) and the National Center for Genome Medicine (NSC102-2319-B-001-001) at Academia Sinica for their support in subject recruitment, genotyping and statistical analysis. The TWSC study was supported by the Academia Sinica Genomic Medicine Multicenter Study, Taiwan (40-05-GMM).

WHII. The WHII study is supported by grants from the Medical Research Council, UK (G0902037), the British Heart Foundation (RG/07/008/23674), the Stroke Association, the National Heart, Lung, and Blood Institute (5RO1HL036310), the National Institute on Aging (5RO1AG13196), the Agency for Health Care Policy Research (HS06516) and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-Economic Status and Health.

YFS. The Young Finns Study has been financially supported by the Academy of Finland through grants 286284 (T.L.), 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi); the Social Insurance Institution of Finland; Kuopio, Tampere and Turku University Hospital Medical Funds (grant X51001 for T.L.); the Juho Vainio Foundation; the Paavo Nurmi Foundation; the Finnish Foundation of Cardiovascular Research (T.L.); the Finnish Cultural Foundation; the Tampere Tuberculosis Foundation (T.L.); the Emil Aaltonen Foundation (T.L.); and the Yrjö Jahnsson Foundation (T.L.).

Author information

Author notes

    • Silke Szymczak

    Present address: Institute of Medical Informatics and Statistics, Christian Albrechts University of Kiel, Kiel, Germany.

    • Norihiro Kato
    • , Marie Loh
    • , Fumihiko Takeuchi
    • , Niek Verweij
    • , Xu Wang
    • , Weihua Zhang
    • , Tanika N Kelly
    • , Danish Saleheen
    • , Benjamin Lehne
    • , Irene Mateo Leach
    • , Yik-Ying Teo
    • , Jiang He
    • , Paul Elliott
    • , E Shyong Tai
    • , Pim van der Harst
    • , Jaspal S Kooner
    •  & John C Chambers

    These authors contributed equally to this work.

Affiliations

  1. Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

    • Norihiro Kato
    • , Fumihiko Takeuchi
    • , Koichi Akiyama
    • , Masato Isono
    •  & Kazuro Shimokawa
  2. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marie Loh
    •  & Marjo-Riitta Jarvelin
  3. Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

    • Marie Loh
    • , Weihua Zhang
    • , Benjamin Lehne
    • , William R Scott
    • , Gianluca Campanella
    • , Marc Chadeau-Hyam
    • , Uzma Afzal
    • , Jagvir Grewal
    • , Paolo Vineis
    • , Paul Elliott
    •  & John C Chambers
  4. Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Singapore.

    • Marie Loh
  5. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Niek Verweij
    • , Irene Mateo Leach
    • , Wiek H van Gilst
    • , Dirk J van Veldhuisen
    •  & Pim van der Harst
  6. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.

    • Xu Wang
    • , Peng Chen
    • , Chiea-Chuen Khor
    • , Ching-Yu Cheng
    • , Woon-Puay Koh
    • , Jeannette Lee
    • , Rob M van Dam
    • , Jianjun Liu
    • , Yik-Ying Teo
    •  & E Shyong Tai
  7. Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK.

    • Weihua Zhang
    • , Sian-Tsung Tan
    • , Uzma Afzal
    • , Jagvir Grewal
    • , Rebecca Mills
    • , Jaspal S Kooner
    •  & John C Chambers
  8. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.

    • Tanika N Kelly
    •  & Jiang He
  9. Center for Non-Communicable Diseases, Karachi, Pakistan.

    • Danish Saleheen
    •  & Rasheed Asif
  10. Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Danish Saleheen
    • , Robin D Young
    •  & John Danesh
  11. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Danish Saleheen
  12. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Alexander W Drong
    •  & Mark I McCarthy
  13. Bioinformatics Support Service, Imperial College London, London, UK.

    • James Abbott
  14. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Simone Wahl
    • , Melanie Waldenberger
    • , Rory Wilson
    •  & Christian Gieger
  15. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Simone Wahl
    • , Annette Peters
    • , Melanie Waldenberger
    • , Rory Wilson
    •  & Christian Gieger
  16. German Center for Diabetes Research (DZD), Neuherberg, Germany.

    • Simone Wahl
  17. National Heart and Lung Institute, Imperial College London, London, UK.

    • Sian-Tsung Tan
    • , William R Scott
    • , James Scott
    •  & Jaspal S Kooner
  18. Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Tarunveer S Ahluwalia
    • , Niels Grarup
    • , Johanne M Justesen
    • , Thomas Sparsø
    • , Torben Hansen
    • , Oluf Pedersen
    •  & Thorkild I A Sørensen
  19. Copenhagen Prospective Studies on Asthma in Childhood (COSPAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

    • Tarunveer S Ahluwalia
  20. Steno Diabetes Center, Gentofte, Denmark.

    • Tarunveer S Ahluwalia
  21. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Marc Jan Bonder
    • , Lude Franke
    • , Cisca Wijmenga
    •  & Pim van der Harst
  22. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Abbas Dehghan
    • , Albert Hofman
    • , André G Uitterlinden
    • , Oscar H Franco
    •  & Aaron Isaacs
  23. Vanderbilt Epidemiology Center, Center for Human Genetics Research, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.

    • Todd L Edwards
  24. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tõnu Esko
    • , Silva Kasela
    • , Evelin Mihailov
    • , Lili Milani
    •  & Andres Metspalu
  25. Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA.

    • Tõnu Esko
  26. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Tõnu Esko
  27. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Tõnu Esko
  28. Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Republic of Korea.

    • Min Jin Go
    • , Yun Kyoung Kim
    • , Joo-Yeon Hwang
    • , Young Jin Kim
    •  & Bong-Jo Kim
  29. Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and Medical Research Council (MRC) Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.

    • Sarah E Harris
  30. Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.

    • Sarah E Harris
    • , Gail Davies
    • , David C M Liewald
    • , John M Starr
    •  & Ian J Deary
  31. Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.

    • Jaana Hartiala
    •  & Hooman Allayee
  32. Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.

    • Jaana Hartiala
    •  & Hooman Allayee
  33. Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.

    • Anuradhani Kasturiratne
    • , Mohitha J Pinidiyapathirage
    •  & Ananda R Wickremasinghe
  34. Genome Institute of Singapore, A*STAR, Singapore.

    • Chiea-Chuen Khor
    • , Rajkumar Dorajoo
    • , Jianjun Liu
    •  & Yik-Ying Teo
  35. Department of Ophthalmology, National University of Singapore, Singapore.

    • Chiea-Chuen Khor
    • , Ching-Yu Cheng
    • , Jiemin Liao
    • , Tien-Yin Wong
    •  & Eranga Vithana
  36. Department of Paediatrics, National University of Singapore, Singapore.

    • Chiea-Chuen Khor
  37. Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.

    • Marcus E Kleber
    • , Graciela Delgado
    • , Tanja B Grammer
    •  & Winfried März
  38. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

    • Huaixing Li
    • , Yiqin Wang
    • , Xingwang Ye
    •  & Xu Lin
  39. Cancer Science Institute of Singapore, National University of Singapore, Singapore.

    • Zuan Yu Mok
    • , Nur Sabrina Sapari
    • , Hong Kiat Ng
    • , Michelle Ann Rozario
    •  & Richie Soong
  40. Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.

    • Masahiro Nakatochi
  41. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Richa Saxena
    •  & Andrew Bjonnes
  42. University of Ottawa Heart Institute, Cardiovascular Research Methods Centre, Ottawa, Ontario, Canada.

    • Alexandre F R Stewart
  43. Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, Ontario, Canada.

    • Alexandre F R Stewart
  44. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Lisette Stolk
    • , André G Uitterlinden
    •  & Joyce B J van Meurs
  45. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Yasuharu Tabara
  46. Singapore Institute for Clinical Sciences (SICS), A*STAR, Singapore.

    • Ai Ling Teh
    • , Yap-Seng Chong
    •  & Joanna D Holbrook
  47. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Ying Wu
    •  & Karen L Mohlke
  48. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

    • Jer-Yuarn Wu
    • , Li-Ching Chang
    • , Chien-Hsiun Chen
    •  & Yuan-Tsong Chen
  49. School of Chinese Medicine, China Medical University, Taichung, Taiwan.

    • Jer-Yuarn Wu
    •  & Chien-Hsiun Chen
  50. State Key Laboratory of Medical Genetics, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Yi Zhang
    •  & Dingliang Zhu
  51. Shanghai Institute of Hypertension, Shanghai, China.

    • Yi Zhang
    •  & Dingliang Zhu
  52. Institute of Epidemiology and Biobank popgen, Christian Albrechts University of Kiel, Kiel, Germany.

    • Imke Aits
    •  & Wolfgang Lieb
  53. Department of Epidemiology and Biostatistics, MRC Health Protection Agency (PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Alexessander Da Silva Couto Alves
    • , Shikta Das
    •  & Marjo-Riitta Jarvelin
  54. Clinical Trials Support Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

    • Jemma C Hopewell
    • , Rory Collins
    • , Sarah Parish
    •  & Robert Clarke
  55. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden.

    • Robert W Koivula
    •  & Paul W Franks
  56. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

    • Jian'an Luan
    •  & Robert A Scott
  57. Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    • , Nina Mononen
    •  & Terho Lehtimäki
  58. Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    • , Nina Mononen
    •  & Terho Lehtimäki
  59. Vietnam National Heart Institute, Bach Mai Hospital, Hanoi, Vietnam.

    • Quang N Nguyen
    • , Loi D Do
    •  & Son T Pham
  60. School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • Mark A Pereira
  61. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

    • Iris Postmus
  62. Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands.

    • Iris Postmus
  63. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.

    • Olli T Raitakari
  64. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

    • Olli T Raitakari
  65. Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.

    • Molly Scannell Bryan
    • , Muhammad G Kibriya
    • , Lin Tong
    •  & Habibul Ahsan
  66. Institute of Genetics and Biophysics A Buzzati-Traverso, CNR, Naples, Italy.

    • Rossella Sorice
    • , Teresa Nutile
    • , Daniela Ruggiero
    •  & Marina Ciullo
  67. Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Vinicius Tragante
    • , Pieter A Doevendans
    •  & Folkert W Asselbergs
  68. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.

    • Michela Traglia
    • , Cinzia F Sala
    •  & Daniela Toniolo
  69. Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Burlo Garofolo', Trieste, Italy.

    • Michela Traglia
  70. University College London Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK.

    • Jon White
  71. Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

    • Ken Yamamoto
  72. Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China.

    • Yonghong Zhang
    • , Hao Peng
    • , Aili Wang
    •  & Zhirong Guo
  73. Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Linda S Adair
  74. UChicago Research Bangladesh, Uttara, Dhaka, Bangladesh.

    • Alauddin Ahmed
    •  & Mahfuzar Rahman
  75. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

    • Tin Aung
    • , Ching-Yu Cheng
    • , Jiemin Liao
    • , Tien-Yin Wong
    • , Eranga Vithana
    •  & Yik-Ying Teo
  76. Metabolic Disease Group, Wellcome Trust Sanger Institute, Cambridge, UK.

    • Inês Barroso
  77. National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Inês Barroso
  78. University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Inês Barroso
  79. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Timothy R Braun
    •  & Dharambir K Sanghera
  80. Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.

    • Hui Cai
    • , Regina Courtney
    • , Xiao-Ou Shu
    •  & Wei Zheng
  81. Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.

    • Hui Cai
    • , Regina Courtney
    • , Xiao-Ou Shu
    •  & Wei Zheng
  82. Centre for Quantitative Medicine, Office of Clinical Sciences, Duke–National University of Singapore Graduate Medical School, Singapore.

    • Ching-Yu Cheng
  83. Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Yap-Seng Chong
  84. Department of Psychology, University of Edinburgh, Edinburgh, UK.

    • Gail Davies
    • , David C M Liewald
    •  & Ian J Deary
  85. Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Ron T Gansevoort
  86. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.

    • Yu-Tang Gao
    •  & Yong-Bing Xiang
  87. Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Dongfeng Gu
  88. Dayanand Medical College and Hospital Unit, Hero DMC Heart Institute, Ludhiana, India.

    • Gurpreet S Wander
    •  & Ralhan Sarju
  89. Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.

    • Anna-Liisa Hartikainen
    •  & Marja Vaarasmaki
  90. Medical Research Center, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
    •  & Marja Vaarasmaki
  91. Unit of Primary Care, Oulu University Hospital, Oulu, Finland.

    • Anna-Liisa Hartikainen
    • , Marja Vaarasmaki
    •  & Marjo-Riitta Jarvelin
  92. Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Stanley L Hazen
    •  & W H Wilson Tang
  93. Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Stanley L Hazen
  94. Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.

    • Jing He
  95. Department of Paediatrics, Yong Loo Lin School of Medicine, Singapore.

    • Chew-Kiat Heng
  96. Human Genetics Center, University of Texas School of Public Health at Houston, Houston, Texas, USA.

    • James E Hixson
  97. University of Southern California Keck School of Medicine, Los Angeles, California, USA.

    • Chris Hsu
    •  & Daniel O Stram
  98. Department of Genetics, Chinese National Human Genomic Center, Shanghai, China.

    • Wei Huang
  99. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.

    • Lise L N Husemoen
    • , Torben Jørgensen
    •  & Allan Linneberg
  100. Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan.

    • Sahoko Ichihara
  101. Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

    • Michiya Igase
    • , Katsuhiko Kohara
    •  & Tetsuro Miki
  102. Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.

    • Tomohiro Katsuya
    •  & E Shyong Tai
  103. Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

    • Tomohiro Katsuya
    •  & Hiromi Rakugi
  104. National Center for Global Health and Medicine, Toyama, Japan.

    • Miyako Kishimoto
    • , Yumi Matsushita
    •  & Hiroshi Kajio
  105. Duke–National University of Singapore Graduate Medical School, Singapore.

    • Woon-Puay Koh
  106. Department of Epidemiology and Public Health, University College London, London, UK.

    • Meena Kumari
    •  & Mika Kivimaki
  107. K.K. Women's and Children's Hospital, Singapore.

    • Kenneth Kwek
  108. University of San Carlos Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines.

    • Nanette R Lee
  109. Department of Anthropology, Sociology and History, University of San Carlos, Cebu City, Philippines.

    • Nanette R Lee
  110. Department of Internal Medicine, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.

    • Tatsuaki Matsubara
  111. Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Thomas Meitinger
  112. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Thomas Meitinger
  113. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Martina Müller-Nurasyid
  114. Department of Medicine I, Ludwig Maximilians University Munich, Munich, Germany.

    • Martina Müller-Nurasyid
  115. German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.

    • Martina Müller-Nurasyid
    •  & Annette Peters
  116. Department of Functional Pathology, Shimane University Faculty of Medicine, Izumo, Japan.

    • Toru Nabika
  117. Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

    • Eitaro Nakashima
  118. Department of Diabetes and Endocrinology, Chubu Rosai Hospital, Nagoya, Japan.

    • Eitaro Nakashima
  119. Heart Centre, Department of Cardiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.

    • Kjell Nikus
  120. Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan.

    • Takayoshi Ohkubo
  121. Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

    • Keizo Ohnaka
  122. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

    • Lavinia Paternoster
    •  & Thorkild I A Sørensen
  123. Research and Evaluation Division, Bangladesh Rehabilitation Assistance Committee (BRAC), Dhaka, Bangladesh.

    • Mahfuzar Rahman
  124. Department of Public Health and Clinical Medicine, Section for Family Medicine, Umeå Universitet, Umeå, Sweden.

    • Olov Rolandsson
    •  & Paul W Franks
  125. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Harold Snieder
  126. Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Wilko Spiering
  127. Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.

    • John M Starr
  128. Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.

    • David J Stott
  129. Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.

    • Takao Sugiyama
  130. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.

    • Silke Szymczak
    •  & Andre Franke
  131. Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • W H Wilson Tang
  132. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.

    • Stella Trompet
    •  & J Wouter Jukema
  133. Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.

    • Väinö Turjanmaa
    •  & Mika Kähönen
  134. Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland.

    • Väinö Turjanmaa
    •  & Mika Kähönen
  135. Department of Health Science, Shiga University of Medical Science, Otsu, Japan.

    • Hirotsugu Ueshima
  136. Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.

    • Hirotsugu Ueshima
  137. Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

    • Satoshi Umemura
  138. Division of Medicine, Turku University Hospital, Turku, Finland.

    • Jorma S Viikari
  139. Department of Medicine, University of Turku, Turku, Finland.

    • Jorma S Viikari
  140. Third Department of Internal Medicine, Shimane University Faculty of Medicine, Izumo, Japan.

    • Shuhei Yamaguchi
  141. Neuroscience and Behavioural Disorders (NBD) Program, Duke–National University of Singapore Graduate Medical School, Singapore.

    • Terri L Young
    •  & Eranga Vithana
  142. Duke Eye Center, Duke University Medical Center, Durham, North Carolina, USA.

    • Terri L Young
  143. Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.

    • Jian-Min Yuan
  144. Bioinformatics Division, Tsinghua National Laboratory for Informatics Science and Technology (TNLIST), Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.

    • Xueya Zhou
  145. Center for Synthetic and Systems Biology, TNLIST, Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.

  146. Department of Psychiatry, University of Hong Kong, Hong Kong.

    • Xueya Zhou
  147. Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of the Netherlands (ICIN)–Netherlands Heart Institute, Utrecht, the Netherlands.

    • Folkert W Asselbergs
    • , J Wouter Jukema
    •  & Pim van der Harst
  148. Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.

    • Folkert W Asselbergs
  149. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Panos Deloukas
  150. King Abdulaziz University, Jeddah, Saudi Arabia.

    • Panos Deloukas
  151. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Paul W Franks
  152. Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, UK.

    • Steve Franks
  153. Hebrew University, School of Public Health, Jerusalem, Israel.

    • Yechiel Friedlander
  154. School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.

    • Myron D Gross
  155. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  156. Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  157. ICIN, Utrecht, the Netherlands.

    • J Wouter Jukema
  158. Ministry of Health and Welfare, Seoul, Republic of Korea.

    • Jong-Young Lee
  159. THERAGEN ETEX Bio Institute, Suwon, Republic of Korea.

    • Jong-Young Lee
  160. Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark.

    • Allan Linneberg
  161. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Allan Linneberg
  162. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.

    • Nilesh J Samani
  163. NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • Nilesh J Samani
  164. Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.

    • Thorkild I A Sørensen
  165. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Kyushu, Japan.

    • Ryoichi Takayanagi
  166. Institute of Molecular Genetics, National Research Council (CNR), Pavia, Italy.

    • Daniela Toniolo
  167. Wellcome Trust Sanger Institute, Hinxton, UK.

    • John Danesh
  168. Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

    • Bastiaan T Heijman
  169. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.

    • Winfried März
  170. Synlab Academy, Synlab Services, Mannheim, Germany.

    • Winfried März
  171. Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Bruce H W Wolffenbuttel
  172. Department of Genome Science, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.

    • Mitsuhiro Yokota
  173. National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.

    • Soterios A Kyrtopoulos
  174. Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands.

    • Jos C S Kleinjans
  175. Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Mark I McCarthy
  176. Department of Pathology, National University of Singapore, Singapore.

    • Richie Soong
  177. National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.

    • Yik-Ying Teo
  178. Life Sciences Institute, National University of Singapore, Singapore.

    • Yik-Ying Teo
  179. Department of Statistics and Applied Probability, National University of Singapore, Singapore.

    • Yik-Ying Teo
  180. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • E Shyong Tai
  181. Imperial College Healthcare NHS Trust, London, UK.

    • Jaspal S Kooner
    •  & John C Chambers

Consortia

  1. BIOS-consortium

    A full list of members appears in the Supplementary Note.

  2. CARDIo GRAMplusCD

    A full list of members appears in the Supplementary Note.

  3. LifeLines Cohort Study

    A full list of members appears in the Supplementary Note.

  4. The InterAct Consortium

    A full list of members appears in the Supplementary Note.

Authors

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Contributions

Participant recruitment, characterization and data generation. Anti-aging study cohort: K. Kohara, M. Igase; Asian Indian Diabetic Heart Study/Sikh Diabetes Study: Y.T., A.B., D.K.S., G.S.W., R. Sarju, R. Saxena, T.R.B.; Biobank-based Integrative Omics Studies Consortium: A.I., B.T.H., M.J.B.; CAGE-Amagasaki: H.R., M. Isono, T.K., F.T., N.K.; CAGE Network: E.N., S.Y., T. Nabika, T. Sugiyama, F.T., N.K.; CAGE-Fukuoka: K.A., K.O., K.Y., R.T.; CAGE-KING: M.N., M.Y., S.I., T. Matsubara; CAGE-Vietnam: H.K., L.D.D., M. Kishimoto, Q.N.N., S.T.P., Y.M.; Cebu Longitudinal Health and Nutrition Survey: K.L.M., L.S.A., N.R.L., Y. Wu; CHD: A.F.R.S., N.J.S., P.D.; INGI Cilento: D.R., M.C., R. Sorice, T. Nutile; EnviroGenoMarkers: G.C., J.C.S.K., M.C.-H., P.V., S.A.K.; Estonian Genome Center of the University of Tartu: A.M., E.M., L.M., T.E.; Finnish Cardiovascular Study: K.N., M. Kähönen, L.-P.L., V. Turjanmaa; Gene Environment Multiphenotype Study: A.A., H. Ahsan, L.T., M.G.K., M.R., M.S.B.; GeneBank Study: H. Allayee, J. Hartiala, S.L.H., W.H.W.T.; Genetic Epidemiology Network of Salt Sensitivity: D.G., J.E.H., Jiang He, T.N.K.; Genetics of Extremely Overweight Young Adults: T.I.A.S., L.P.; Gene × Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk: I.B., P.W.F., R.W.K., O.R.; DIABNORD: P.W.F., R.W.K., O.R.; Growing Up in Singapore Towards Healthy Outcomes: A.L.T., J.D.H., K. Kwek, Y.-S.C.; Health Examinee (HEXA) shared control study: J.-Y.L., Y.J.K., Y.K.K.; Health2006: A.L., J.M.J., L.L.N.H., T.H., T.S.A.; Heart Protection Study: J.C.H., R. Clarke, R. Collins, S.P.; INGI Val Borbera: C.F.S., D.T., M.T.; Inter99: N.G., O.P., T. Sparsø, T.J., T.S.A.; InterAct: J. Luan, R.A.S.; Japanese Millennium Genome Project: Y.T., H.U., S.U., T. Miki, T.O.; KORA: A.P., C.G., M.M.-N., M.W., R.W., S.W., T. Meitinger; Korea Association Resource study: B.-J.K., J.-Y.H., M.J.G.; LifeLines Cohort Study: B.H.W.W., C.W., D.J.v.V., H.S., L.F., P.v.d.H.; London Life Sciences Population study: B.L., J.A., J.C.C., J.G., J.S., J.S.K., M.L., P.E., R.M., S.-T.T., U.A., W.R.S., W. Zhang, A.W.D., M.I.M.; Lothian Birth Cohorts: D.C.M.L., G. Davies, I.J.D., J.M.S., S.E.H.; Ludwigshafen Risk and Cardiovascular Health Study: G. Delgado, M.E.K., T.B.G., W.M.; Northern Finland Birth Cohort 1986: A.D.S.C.A., A.-L.H., M.-R.J., M.V., S.D., S.F.; Nutrition and Health of Aging Population in China: H.L., X.L., X.Y., Y. Wang; Pakistan Risk Of Myocardial Infarction Study: D.S., J.D., R.A., R.D.Y.; POPGEN study: A.F., I.A., S.S., W.L.; Prevention of Renal and Vascular End-Stage Disease: I.M.L., N.V., R.T.G., W.H.v.G.; Prospective Study of Pravastatin in the Elderly at Risk: D.J.S., I.P., S.T., J.W.J.; Ragama Health Study: A.K., A.R.W., K.S., M.J.P.; Rotterdam Study: A.D., A.G.U., A.H., J.B.J.v.M., L.S., O.H.F.; Secondary Manifestations of Arterial Disease: F.W.A., P.A.D., V. Tragante, W.S.; Shanghai Men's and Women's Health Studies: H.C., Jing He, R. Courtney, T.L.E., W. Zheng, X.-O.S., Y.-B.X., Y.-T.G.; Shanghai-Ruijin Study: D.Z., W.H., X.Z., Yi Zhang; Singapore Chinese Eye Study: C.-C.K., C.-Y.C., J. Liu, T.-Y.W.; Singapore Chinese Health Study: C.H., D.O.S., M.A.P., M.D.G., C.-K.H., J.-M.Y., R.D., R.M.v.D., W.-P.K., Y.F.; Singapore Indian Eye Study: E.S.T., E.V., J. Liao, T.A.; Singapore Malay Eye Study: Y.-Y.T.; Singapore Prospective Study Program: J. Lee, P.C., T.L.Y., X.W.; Suzhou Metabolic Syndrome Study: A.W., H.P., Yonghong Zhang, Z.G.; Taiwan Super Control Study: C.-H.C., J.-Y.W., L.-C.C., Y.-T.C.; Tartu: S.K.; Whitehall II study: J.W., M. Kivimaki, M. Kumari; Young Finns Study: J.S.V., N.M., O.T.R., T.L.

Functional genomics and targeted resequencing: M.L., H.K.N., M.A.R., Z.Y.M., R. Soong, N.S.S. Statistical analyses: M.L., F.T., N.V., X.W., W. Zhang, B.L., I.M.L., N.K., J.C.C.

Steering and manuscript writing committee: N.K., M.L., F.T., T.N.K., Y.-Y.T., Jiang He, P.E., E.S.T., P.v.d.H., J.S.K., J.C.C.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Norihiro Kato or Jiang He or Paul Elliott or E Shyong Tai or Pim van der Harst or Jaspal S Kooner or John C Chambers.

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https://doi.org/10.1038/ng.3405

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