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

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 BonderPeng 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

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161 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1282-1293
Number of pages12
JournalNature Genetics
Volume47
Issue number11
DOIs
Publication statusPublished - 2015 Nov 1

ASJC Scopus subject areas

  • Genetics

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