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

2015; Nature Portfolio; Volume: 47; Issue: 11 Linguagem: Inglês

10.1038/ng.3405

1546-1718

Norihiro Kato, Marie Loh, Fumihiko Takeuchi, Niek Verweij, Xu Wang, Weihua Zhang, Tanika N Kelly, Danish Saleheen, Benjamin Lehne, Irene Mateo Leach, Alexander 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 Couto Alves, Shikta Das, Rajkumar Dorajoo, Jemma C Hopewell, Yun Kyoung Kim, Robert W Koivula, Jian’an Luan, Leo‐Pekka Lyytikäinen, Quang N Nguyen, Mark A. Pereira, Iris Postmus, Olli T Raitakari, 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., Pieter A. Doevendans, Ron T. Gansevoort, Yu-Tang Gao, Tanja B. Grammer, Niels Grarup, Jagvir Grewal, Dongfeng Gu, Gurpreet S Wander, Anna-Liisa Hartikainen, Stanley L. Hazen, Jing He, Chew‐Kiat Heng, James E. Hixson, Albert Hofman, Chris Hsu, Wei Huang, Lise Lotte N. Husemoen, Joo‐Yeon Hwang, Sahoko Ichihara, Michiya Igase, Masato Isono, Johanne Marie Justesen, Tomohiro Katsuya, Muhammad G Kibriya, Young Jin Kim, Miyako Kishimoto, Woon‐Puay Koh, Katsuhiko Kohara, Meena Kumari, Kenneth Kwek, Sang Lee, Jeannette Lee, Jiemin Liao, Wolfgang Lieb, David C. 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 T Pham, Janani Pinidiyapathirage, Mahfuzar Rahman, Hiromi Rakugi, Olov Rolandsson, Michelle Ann Rozario, Daniela Ruggiero, Cinzia Sala, Sarju Ralhan, Kazuro Shimokawa, Harold Snieder, Thomas Sparsø, Wilko Spiering, John M. Starr, David J. Stott, Daniel O. Stram, Takao Sugiyama, Silke Szymczak, W.H. Wilson Tang, Tong Lin, Stella Trompet, Väinö Turjanmaa, Hirotsugu Ueshima, André G. Uitterlinden, Satoshi Umemura, Marja Vääräsmäki, Rob M. van Dam, Wiek H. van Gilst, Dirk J. van Veldhuisen, Jorma Viikari, Mélanie Waldenberger, Yiqin Wang, Aili Wang, Rory Wilson, Tien Yin Wong, Yong-Bing Xiang, Shuhei Yamaguchi, Xingwang Ye, Robin Young, Terri L. Young, Jian‐Min Yuan, Xueya Zhou, Folkert W. Asselbergs, Marina Ciullo, Robert B. Clarke, Panos Deloukas, André Franke, Paul W. Franks, Steve Franks, Yechiel Friedlander, Myron D. Gross, Zhirong Guo, Torben Hansen, Marjo‐Riitta Järvelin, Torben Jørgensen, J. Wouter Jukema, Mika Kähönen, Hiroshi Kajio, Mika Kivimäki, Jong‐Young Lee, Terho Lehtimäki, Allan Linneberg, Tetsuro Miki, Oluf Pedersen, Nilesh J. Samani, Thorkild I. A. Sörensen, Ryoichi Takayanagi, Daniela Toniolo, Habibul Ahsan, Hooman Allayee, Yuan-Tsong Chen, John Danesh, Ian J. Deary, Oscar H. Franco, Lude Franke, Bastiaan T Heijman, Joanna D. Holbrook, Aaron Isaacs, Bong‐Jo Kim, Xu Lin, Jianjun Liu, Winfried März, Andres Metspalu, Karen L. Mohlke, Dharambir K. Sanghera, Xiao‐Ou Shu, Joyce B. J. van Meurs, Eranga N. Vithana, Ananda R. Wickremasinghe, Cisca Wijmenga, Bruce H. R. Wolffenbuttel, Mitsuhiro Yokota, Wei Zheng, Dingliang Zhu, Paolo Vineis, Soterios Α. Kyrtopoulos, Jos Kleinjans, Mark I. McCarthy, Richie Soong, Christian Gieger, Berthold Lausen, Yik‐Ying Teo, Jiang He, Paul Elliott, E Shyong Tai, Pim van der Harst, Jaspal S. Kooner, John C. Chambers,

Birth, Development, and Health

John Chambers, Jaspal Kooner, Pim van der Harst, Shyong Tai, Paul Elliott, Jiang He, Norihiro Kato and colleagues performed a genome-wide association study of blood pressure phenotypes in individuals of European, East Asian and South Asian ancestry. They find trait-associated SNPs at 12 loci, some of which are associated with methylation at nearby CpG sites. 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.