Norihiro Kato, Marie Loh, Fumihiko Takeuchi, Niek Verweij, Xu Wang, Weihua Zhang, Tanika NKelly, Danish Saleheen, Benjamin Lehne, Irene Mateo Leach, Alexander W. Drong, James Abbott, Simone Wahl, Sian-Tsung Tan, William R. Scott, Gianluca Campanella, Marc Chadeau-Hyam, Uzma Afzal, Tarunveer S. Ahluwalia, Marc Jan Bonder, Peng Chen, Abbas Dehghan, Todd L. Edwards, Tõnu Esko, Min Jin Go, Sarah E. Harris, Jaana Hartiala, Silva Kasela, Anuradhani Kasturiratne, Chiea-Chuen Khor, Marcus E. Kleber, Huaixing Li, Zuan Yu Mok, Masahiro Nakatochi, Nur Sabrina Sapari, Richa Saxena, Alexandre F.R. Stewart, Lisette Stolk, Yasuharu Tabara, Ai Ling Teh, Ying Wu, Jer-Yuarn Wu, Yi Zhang, Imke Aits, Alexessander Da Silva Couto Alves, Shikta Das, Rajkumar Dorajoo, Jemma CHopewell, Yun Kyoung Kim, Robert WKoivula, Jian'An Luan, Leo-Pekka Lyytikäinen, Quang NNguyen, Mark A. Pereira, Iris Postmus, Olli TRaitakari, Molly Scannell Bryan, Robert A. Scott, Rossella Sorice, Vinicius Tragante, Michela Traglia, Jon White, Ken Yamamoto, Yonghong Zhang, Linda S. Adair, Alauddin Ahmed, Koichi Akiyama, Rasheed Asif, Tin Aung, Inês Barroso, Andrew Bjonnes, Timothy R. Braun, Hui Cai, Li-Ching Chang, Chien-Hsiun Chen, Ching-Yu Cheng, Yap-Seng Chong, Rory Collins, Regina Courtney, Gail Davies, Graciela Delgado, Loi D. Do, Pieter A. Doevendans, Ron T. Gansevoort, Yu-Tang Gao, Tanja B. Grammer, Niels Grarup, Jagvir Grewal, Dongfeng Gu, Gurpreet SWander, Anna-Liisa Hartikainen, Stanley L. Hazen, Jing He, Chew-Kiat Heng, E. James Ames Hixso, Albert Hofman, Chris Hsu, Wei Huang, Lise L.N. Husemoen, Joo-Yeon Hwang, Sahoko Ichihara, Michiya Igase, Masato Isono, Johanne M. Justesen, Tomohiro Katsuya, Muhammad GKibriya, Young Jin Kim, Miyako Kishimoto, Woon-Puay Koh, Katsuhiko Kohara, Meena Kumari, Kenneth Kwek, Nanette R. Lee, Jeannette Lee, Jiemin Liao, Wolfgang Lieb, David C.M. Liewald, Tatsuaki Matsubara, Yumi Matsushita, Thomas Meitinger, Evelin Mihailov, Lili Milani, Rebecca Mills, Nina Mononen, Martina Müller-Nurasyid, Toru Nabika, Eitaro Nakashima, Hong Kiat Ng, Kjell Nikus, Teresa Nutile, Takayoshi Ohkubo, Keizo Ohnaka, Sarah Parish, Lavinia Paternoster, Hao Peng, Annette Peters, Son TPham, Mohitha J. Pinidiyapathirage, Mahfuzar Rahman, Hiromi Rakugi, Olov Rolandsson, Michelle Ann Rozario, Daniela Ruggiero, Cinzia F. Sala, Ralhan Sarju, Kazuro Shimokawa, Harold Snieder, Thomas SparsØ, Wilko Spiering, John M. Starr, David J. Stott, Daniel OStram, Takao Sugiyama, Silke Szymczak, W.H. Wilson Tang, Lin Tong, Stella Trompet, Väinö Turjanmaa, Hirotsugu Ueshima, André G. Uitterlinden, Satoshi Umemura, Marja Vaarasmaki, Rob Mvan Dam, Wiek H. Van Gilst, Dirk J. Van Veldhuisen, Jorma S. Viikari, Melanie Waldenberger, Yiqin Wang, Aili Wang, Rory Wilson, Tien-Yin Wong, Yong-Bing Xiang, Shuhei Yamaguchi, Xingwang Ye, Robin D. Young, Terri L. Young, Jian-Min Yuan, Xueya Zhou, Folkert W. Asselbergs, Marina Ciullo, Robert Clarke, Panos Deloukas, Andre Franke, W. Frank Paul, Steve Franks, Yechiel Friedlander, Myron D. Gross, Zhirong Guo, Torben Hansen, Marjo-Riitta Jarvelin, Torben JØrgensen, J. Wouter Jukema, Mika Kähönen, Hiroshi Kajio, Mika Kivimaki, Jong-Young Lee, Terho Lehtimäki, Allan Linneberg, Tetsuro Miki, Oluf Pedersen, Nilesh J. Samani, Thorkild I.A. SØrensen, Ryoichi Takayanagi, Daniela Toniolo, Habibul Ahsan, Hooman Allayee, Yuan-Tsong Chen, John Danesh, Ian J. Deary, Oscar H. Franco, Lude Franke, Bastiaan THeijman, Joanna D. Holbrook, Aaron Isaacs, Bong-Jo Kim, Xu Lin, Jianjun Liu, Winfried März, Andres Metspalu, Karen L. Mohlke, K. Sangher, Dharambir Harambir, Xiao-Ou Shu, Joyce B.J. Van Meurs, Eranga Vithana, Ananda R. Wickremasinghe, Cisca Wijmenga, Bruce H.W. Wolffenbuttel, Mitsuhiro Yokota, Wei Zheng, Dingliang Zhu, Paolo Vineis, Soterios A. Kyrtopoulos, Jos C.S. Kleinjans, Mark I. McCarthy, Richie Soong, Christian Gieger, James Scott, Yik-Ying Teo, Jiang He, Paul Elliott, E. Shyong Tai, Pim Van Der Harst, Jaspal S. Kooner, John C. Chambers
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. © 2015 Nature America, Inc.
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Institute of Health Sciences, University of Oulu, Oulu, Finland; Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom; Translational Laboratory in Genetic Medicine, Agency for Science,Technology and Research (A STAR), Singapore, Singapore; Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore; Ealing Hospital National Health Service (NHS) Trust, Middlesex, United Kingdom; Department of Epidemiology, Tulane University, School of Public Health and Tropical Medicine, New Orleans, LA, United States; Center for Non-Communicable Diseases, Karachi, Pakistan; Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Bioinformatics Support Service, Imperial College London, London, United Kingdom; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; National Heart and Lung Institute, Imperial College London, London, United Kingdom; Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark; Copenhagen Prospective Studies on Asthma in Childhood (COSPAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center, Gentofte, Denmark; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands; Vanderbilt Epidemiology Center, Department of Medicine, Vanderbilt University, Nashville, TN, United States; Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Children's Hospital Boston, Boston, MA, United States; Department of Genetics, Harvard Medical School, Boston, MA, United States; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States; Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, South Korea; Medical Genetics Section, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Department of Preventive Medicine, University of Southern California Keck, School of Medicine, Los Angeles, CA, United States; Institute for Genetic Medicine, University of Southern California Keck, School of Medicine, Los Angeles, CA, United States; Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Genome Institute of Singapore, A STAR, Singapore, Singapore; Department of Ophthalmology, National University of Singapore, Singapore, Singapore; Department of Paediatrics, National University of Singapore, Singapore, Singapore; Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai, China; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States; University of Ottawa Heart Institute, Cardiovascular Research Methods Centre, Ottawa, ON, Canada; Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, ON, Canada; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Genomic Medicine, Kyoto University, Graduate School of Medicine, Kyoto, Japan; Singapore Institute for Clinical Sciences (SICS), A STAR, Singapore, Singapore; Department of Genetics, University of North Carolina, Chapel Hill, NC, United States; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan; State Key Laboratory of Medical Genetics, Shanghai Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Hypertension, Shanghai, China; Institute of Epidemiology and Biobank popgen, Christian Albrechts University of Kiel, Kiel, Germany; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Clinical Trials Support Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skne University Hospital Malmö, Malmö, Sweden; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; Department of Clinical Chemistry, University of Tampere, School of Medicine, Tampere, Finland; Vietnam National Heart Institute, Bach Mai Hospital, Hanoi, Viet Nam; School of Public Health, University of Minnesota, Minneapolis, MN, United States; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands; Netherlands Consortium for Healthy Ageing, Leiden, Netherlands; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Public Health Sciences, University of Chicago, Chicago, IL, United States; Institute of Genetics and Biophysics A Buzzati-Traverso, CNR, Naples, Italy; Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Burlo Garofolo', Trieste, Italy; University College London Genetics Institute, Department of Genetics,Environment and Evolution, University College London, London, United Kingdom; Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China; Department of Nutrition, University of North Carolina, Chapel Hill, NC, United States; UChicago Research Bangladesh, Uttara, Dhaka, Bangladesh; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore; Metabolic Disease Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom; National Institute for Health Research (NIHR), Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, United Kingdom; University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States; Department of Medicine, Vanderbilt University, Nashville, TN, United States; Vanderbilt-Ingram Cancer Center, Department of Medicine, Vanderbilt University, Nashville, TN, United States; Centre for Quantitative Medicine, Duke-National University of Singapore, Graduate Medical School, Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China; Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Dayanand Medical College and Hospital Unit, Hero DMC Heart Institute, Ludhiana, India; Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland; Medical Research Center, University of Oulu, Oulu, Finland; Unit of Primary Care, Oulu University Hospital, Oulu, Finland; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, United States; Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States; Department of Biostatistics, Vanderbilt University, Nashville, TN, United States; Department of Paediatrics, Yong Loo Lin School of Medicine, Singapore, Singapore; Human Genetics Center, University of Texas, School of Public Health at Houston, Houston, TX, United States; University of Southern California, Keck School of Medicine, Los Angeles, CA, United States; Department of Genetics, Chinese National Human Genomic Center, Shanghai, China; Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark; Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan; Department of Geriatric Medicine, Ehime University, Graduate School of Medicine, Toon, Ehime, Japan; Department of Clinical Gene Therapy, Osaka University, Graduate School of Medicine, Suita, Japan; Department of Geriatric Medicine and Nephrology, Osaka University, Graduate School of Medicine, Suita, Japan; National Center for Global Health and Medicine, Toyama, Japan; Duke-National University of Singapore, Graduate Medical School, Singapore, Singapore; Department of Epidemiology and Public Health, University College London, London, United Kingdom; K.K. Women's and Children's Hospital, Singapore, Singapore; University of San Carlos Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines; Department of Anthropology,Sociology and History, University of San Carlos, Cebu City, Philippines; Department of Internal Medicine, Aichi-Gakuin University, School of Dentistry, Nagoya, Japan; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig Maximilians University Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Munich, Germany; Department of Functional Pathology, Shimane University, Faculty of Medicine, Izumo, Japan; Division of Endocrinology and Diabetes, Nagoya University, Graduate School of Medicine, Nagoya, Japan; Department of Diabetes and Endocrinology, Chubu Rosai Hospital, Nagoya, Japan; Department of Cardiology, Tampere University Hospital, University of Tampere, Tampere, Finland; Department of Hygiene and Public Health, Teikyo University, School of Medicine, Tokyo, Japan; Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Research and Evaluation Division, Bangladesh Rehabilitation Assistance Committee (BRAC), Dhaka, Bangladesh; Department of Public Health and Clinical Medicine, Section for Family Medicine, Ume Universitet, Ume, Sweden; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, Netherlands; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom; Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan; Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States; Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands; Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; Department of Clinical Physiology, University of Tampere, School of Medicine, Tampere, Finland; Department of Health Science, Shiga University of Medical Science, Otsu, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan; Department of Medical Science and Cardiorenal Medicine, Yokohama City University, Graduate School of Medicine, Yokohama, Japan; Division of Medicine, Turku University Hospital, Turku, Finland; Department of Medicine, University of Turku, Turku, Finland; Third Department of Internal Medicine, Shimane University, Faculty of Medicine, Izumo, Japan; Neuroscience and Behavioural Disorders (NBD) Program, Duke-National University of Singapore, Graduate Medical School, Singapore, Singapore; Duke Eye Center, Duke University Medical Center, Durham, NC, United States; Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States; Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China; Center for Synthetic and Systems Biology, Department of Automation, Tsinghua University, Beijing, China; Department of Psychiatry, University of Hong Kong, Hong Kong, Hong Kong; Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of the Netherlands (ICIN)-Netherlands Heart Institute, Utrecht, Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; King Abdulaziz University, Jeddah, Saudi Arabia; Department of Nutrition, Harvard School of Public Health, Boston, MA, United States; Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom; Hebrew University, School of Public Health, Jerusalem, Israel; School of Medicine, University of Minnesota, Minneapolis, MN, United States; Biocenter Oulu, University of Oulu, Oulu, Finland; Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland; ICIN, Utrecht, Netherlands; Ministry of Health and Welfare, Seoul, South Korea; THERAGEN ETEX Bio Institute, Suwon, South Korea; Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom; Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Kyushu, Japan; Institute of Molecular Genetics, National Research Council (CNR), Pavia, Italy; Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; Synlab Academy, Synlab Services, Mannheim, Germany; Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Department of Genome Science, Aichi-Gakuin University, School of Dentistry, Nagoya, Japan; National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece; Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Department of Pathology, National University of Singapore, Singapore, Singapore; National University of Singapore, Graduate School for Integrative Science and Engineering, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore; Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Imperial College Healthcare NHS Trust, London, United Kingdom; Institute of Medical Informatics and Statistics, Christian Albrechts University of Kiel, Kiel, Germany
