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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

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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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Figure 1: Regional plots for the three newly identified loci associated with SBP.
Figure 2: Regional plots for the two newly identified loci associated with DBP.
Figure 3: Regional plots for the four newly identified loci associated with pulse pressure.
Figure 4: Regional plots for the three newly identified loci associated with MAP.
Figure 5: DNA methylation as a potential mediator of the relationship between sentinel SNPs and blood pressure at the loci reaching genome-wide significance in our study.

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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

  1. Silke Szymczak

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

  2. 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 and John C Chambers: These authors contributed equally to this work.

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

Authors and 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. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Center for Human Genetics Research, 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. Nuffield Department of Population Health, Clinical Trials Support Unit (CTSU), 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. Department of Genetics, University College London Genetics Institute, 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. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA

    Hui Cai, Regina Courtney, Xiao-Ou Shu & Wei Zheng

  81. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, 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. Department of Cardiology, Heart Centre, 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, Department of Automation, Tsinghua National Laboratory for Informatics Science and Technology (TNLIST), Ministry of Education Key Laboratory of Bioinformatics, Tsinghua University, Beijing, China

    Xueya Zhou

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

    Xueya Zhou

  146. 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

  147. Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK

    Folkert W Asselbergs

  148. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Panos Deloukas

  149. King Abdulaziz University, Jeddah, Saudi Arabia

    Panos Deloukas

  150. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA

    Paul W Franks

  151. Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, UK

    Steve Franks

  152. Hebrew University, School of Public Health, Jerusalem, Israel

    Yechiel Friedlander

  153. School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA

    Myron D Gross

  154. Biocenter Oulu, University of Oulu, Oulu, Finland

    Marjo-Riitta Jarvelin

  155. Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland

    Marjo-Riitta Jarvelin

  156. ICIN, Utrecht, the Netherlands

    J Wouter Jukema

  157. Ministry of Health and Welfare, Seoul, Republic of Korea

    Jong-Young Lee

  158. THERAGEN ETEX Bio Institute, Suwon, Republic of Korea

    Jong-Young Lee

  159. Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark

    Allan Linneberg

  160. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Allan Linneberg

  161. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK

    Nilesh J Samani

  162. NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK

    Nilesh J Samani

  163. Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark

    Thorkild I A Sørensen

  164. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Kyushu, Japan

    Ryoichi Takayanagi

  165. Institute of Molecular Genetics, National Research Council (CNR), Pavia, Italy

    Daniela Toniolo

  166. Wellcome Trust Sanger Institute, Hinxton, UK

    John Danesh

  167. Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands

    Bastiaan T Heijman

  168. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

    Winfried März

  169. Synlab Academy, Synlab Services, Mannheim, Germany

    Winfried März

  170. Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    Bruce H W Wolffenbuttel

  171. Department of Genome Science, Aichi-Gakuin University School of Dentistry, Nagoya, Japan

    Mitsuhiro Yokota

  172. National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece

    Soterios A Kyrtopoulos

  173. Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands

    Jos C S Kleinjans

  174. Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK

    Mark I McCarthy

  175. Department of Pathology, National University of Singapore, Singapore

    Richie Soong

  176. National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore

    Yik-Ying Teo

  177. Life Sciences Institute, National University of Singapore, Singapore

    Yik-Ying Teo

  178. Department of Statistics and Applied Probability, National University of Singapore, Singapore

    Yik-Ying Teo

  179. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    E Shyong Tai

  180. Imperial College Healthcare NHS Trust, London, UK

    Jaspal S Kooner & John C Chambers

Authors
  1. Norihiro Kato
  2. Marie Loh
  3. Fumihiko Takeuchi
  4. Niek Verweij
  5. Xu Wang
  6. Weihua Zhang
  7. Tanika N Kelly
  8. Danish Saleheen
  9. Benjamin Lehne
  10. Irene Mateo Leach
  11. Alexander W Drong
  12. James Abbott
  13. Simone Wahl
  14. Sian-Tsung Tan
  15. William R Scott
  16. Gianluca Campanella
  17. Marc Chadeau-Hyam
  18. Uzma Afzal
  19. Tarunveer S Ahluwalia
  20. Marc Jan Bonder
  21. Peng Chen
  22. Abbas Dehghan
  23. Todd L Edwards
  24. Tõnu Esko
  25. Min Jin Go
  26. Sarah E Harris
  27. Jaana Hartiala
  28. Silva Kasela
  29. Anuradhani Kasturiratne
  30. Chiea-Chuen Khor
  31. Marcus E Kleber
  32. Huaixing Li
  33. Zuan Yu Mok
  34. Masahiro Nakatochi
  35. Nur Sabrina Sapari
  36. Richa Saxena
  37. Alexandre F R Stewart
  38. Lisette Stolk
  39. Yasuharu Tabara
  40. Ai Ling Teh
  41. Ying Wu
  42. Jer-Yuarn Wu
  43. Yi Zhang
  44. Imke Aits
  45. Alexessander Da Silva Couto Alves
  46. Shikta Das
  47. Rajkumar Dorajoo
  48. Jemma C Hopewell
  49. Yun Kyoung Kim
  50. Robert W Koivula
  51. Jian'an Luan
  52. Leo-Pekka Lyytikäinen
  53. Quang N Nguyen
  54. Mark A Pereira
  55. Iris Postmus
  56. Olli T Raitakari
  57. Molly Scannell Bryan
  58. Robert A Scott
  59. Rossella Sorice
  60. Vinicius Tragante
  61. Michela Traglia
  62. Jon White
  63. Ken Yamamoto
  64. Yonghong Zhang
  65. Linda S Adair
  66. Alauddin Ahmed
  67. Koichi Akiyama
  68. Rasheed Asif
  69. Tin Aung
  70. Inês Barroso
  71. Andrew Bjonnes
  72. Timothy R Braun
  73. Hui Cai
  74. Li-Ching Chang
  75. Chien-Hsiun Chen
  76. Ching-Yu Cheng
  77. Yap-Seng Chong
  78. Rory Collins
  79. Regina Courtney
  80. Gail Davies
  81. Graciela Delgado
  82. Loi D Do
  83. Pieter A Doevendans
  84. Ron T Gansevoort
  85. Yu-Tang Gao
  86. Tanja B Grammer
  87. Niels Grarup
  88. Jagvir Grewal
  89. Dongfeng Gu
  90. Gurpreet S Wander
  91. Anna-Liisa Hartikainen
  92. Stanley L Hazen
  93. Jing He
  94. Chew-Kiat Heng
  95. James E Hixson
  96. Albert Hofman
  97. Chris Hsu
  98. Wei Huang
  99. Lise L N Husemoen
  100. Joo-Yeon Hwang
  101. Sahoko Ichihara
  102. Michiya Igase
  103. Masato Isono
  104. Johanne M Justesen
  105. Tomohiro Katsuya
  106. Muhammad G Kibriya
  107. Young Jin Kim
  108. Miyako Kishimoto
  109. Woon-Puay Koh
  110. Katsuhiko Kohara
  111. Meena Kumari
  112. Kenneth Kwek
  113. Nanette R Lee
  114. Jeannette Lee
  115. Jiemin Liao
  116. Wolfgang Lieb
  117. David C M Liewald
  118. Tatsuaki Matsubara
  119. Yumi Matsushita
  120. Thomas Meitinger
  121. Evelin Mihailov
  122. Lili Milani
  123. Rebecca Mills
  124. Nina Mononen
  125. Martina Müller-Nurasyid
  126. Toru Nabika
  127. Eitaro Nakashima
  128. Hong Kiat Ng
  129. Kjell Nikus
  130. Teresa Nutile
  131. Takayoshi Ohkubo
  132. Keizo Ohnaka
  133. Sarah Parish
  134. Lavinia Paternoster
  135. Hao Peng
  136. Annette Peters
  137. Son T Pham
  138. Mohitha J Pinidiyapathirage
  139. Mahfuzar Rahman
  140. Hiromi Rakugi
  141. Olov Rolandsson
  142. Michelle Ann Rozario
  143. Daniela Ruggiero
  144. Cinzia F Sala
  145. Ralhan Sarju
  146. Kazuro Shimokawa
  147. Harold Snieder
  148. Thomas Sparsø
  149. Wilko Spiering
  150. John M Starr
  151. David J Stott
  152. Daniel O Stram
  153. Takao Sugiyama
  154. Silke Szymczak
  155. W H Wilson Tang
  156. Lin Tong
  157. Stella Trompet
  158. Väinö Turjanmaa
  159. Hirotsugu Ueshima
  160. André G Uitterlinden
  161. Satoshi Umemura
  162. Marja Vaarasmaki
  163. Rob M van Dam
  164. Wiek H van Gilst
  165. Dirk J van Veldhuisen
  166. Jorma S Viikari
  167. Melanie Waldenberger
  168. Yiqin Wang
  169. Aili Wang
  170. Rory Wilson
  171. Tien-Yin Wong
  172. Yong-Bing Xiang
  173. Shuhei Yamaguchi
  174. Xingwang Ye
  175. Robin D Young
  176. Terri L Young
  177. Jian-Min Yuan
  178. Xueya Zhou
  179. Folkert W Asselbergs
  180. Marina Ciullo
  181. Robert Clarke
  182. Panos Deloukas
  183. Andre Franke
  184. Paul W Franks
  185. Steve Franks
  186. Yechiel Friedlander
  187. Myron D Gross
  188. Zhirong Guo
  189. Torben Hansen
  190. Marjo-Riitta Jarvelin
  191. Torben Jørgensen
  192. J Wouter Jukema
  193. Mika Kähönen
  194. Hiroshi Kajio
  195. Mika Kivimaki
  196. Jong-Young Lee
  197. Terho Lehtimäki
  198. Allan Linneberg
  199. Tetsuro Miki
  200. Oluf Pedersen
  201. Nilesh J Samani
  202. Thorkild I A Sørensen
  203. Ryoichi Takayanagi
  204. Daniela Toniolo
  205. Habibul Ahsan
  206. Hooman Allayee
  207. Yuan-Tsong Chen
  208. John Danesh
  209. Ian J Deary
  210. Oscar H Franco
  211. Lude Franke
  212. Bastiaan T Heijman
  213. Joanna D Holbrook
  214. Aaron Isaacs
  215. Bong-Jo Kim
  216. Xu Lin
  217. Jianjun Liu
  218. Winfried März
  219. Andres Metspalu
  220. Karen L Mohlke
  221. Dharambir K Sanghera
  222. Xiao-Ou Shu
  223. Joyce B J van Meurs
  224. Eranga Vithana
  225. Ananda R Wickremasinghe
  226. Cisca Wijmenga
  227. Bruce H W Wolffenbuttel
  228. Mitsuhiro Yokota
  229. Wei Zheng
  230. Dingliang Zhu
  231. Paolo Vineis
  232. Soterios A Kyrtopoulos
  233. Jos C S Kleinjans
  234. Mark I McCarthy
  235. Richie Soong
  236. Christian Gieger
  237. James Scott
  238. Yik-Ying Teo
  239. Jiang He
  240. Paul Elliott
  241. E Shyong Tai
  242. Pim van der Harst
  243. Jaspal S Kooner
  244. John C Chambers

Consortia

BIOS-consortium

CARDIo GRAMplusCD

LifeLines Cohort Study

The InterAct Consortium

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.

Corresponding authors

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

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures (download PDF )

Supplementary Figures 1–15 and Supplementary Note. (PDF 4273 kb)

Supplementary Tables 1–19 (download XLSX )

Supplementary Tables 1–19. (XLSX 311 kb)

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Kato, N., Loh, M., Takeuchi, F. et al. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nat Genet 47, 1282–1293 (2015). https://doi.org/10.1038/ng.3405

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