跨祖先全基因组关联研究确定了12个影响血压的基因位点，并表明DNA甲基化发挥了作用。
Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.
作者信息
Kato Norihiro, Loh Marie, Takeuchi Fumihiko, Verweij Niek, Wang Xu, Zhang Weihua, Kelly Tanika N, Saleheen Danish, Lehne Benjamin, Leach Irene Mateo, Drong Alexander W, Abbott James, Wahl Simone, Tan Sian-Tsung, Scott William R, Campanella Gianluca, Chadeau-Hyam Marc, Afzal Uzma, Ahluwalia Tarunveer S, Bonder Marc Jan, Chen Peng, Dehghan Abbas, Edwards Todd L, Esko Tõnu, Go Min Jin, Harris Sarah E, Hartiala Jaana, Kasela Silva, Kasturiratne Anuradhani, Khor Chiea-Chuen, Kleber Marcus E, Li Huaixing, Yu Mok Zuan, Nakatochi Masahiro, Sapari Nur Sabrina, Saxena Richa, Stewart Alexandre F R, Stolk Lisette, Tabara Yasuharu, Teh Ai Ling, Wu Ying, Wu Jer-Yuarn, Zhang Yi, Aits Imke, Da Silva Couto Alves Alexessander, Das Shikta, Dorajoo Rajkumar, Hopewell Jemma C, Kim Yun Kyoung, Koivula Robert W, Luan Jian'an, Lyytikäinen Leo-Pekka, Nguyen Quang N, Pereira Mark A, Postmus Iris, Raitakari Olli T, Scannell Bryan Molly, Scott Robert A, Sorice Rossella, Tragante Vinicius, Traglia Michela, White Jon, Yamamoto Ken, Zhang Yonghong, Adair Linda S, Ahmed Alauddin, Akiyama Koichi, Asif Rasheed, Aung Tin, Barroso Inês, Bjonnes Andrew, Braun Timothy R, Cai Hui, Chang Li-Ching, Chen Chien-Hsiun, Cheng Ching-Yu, Chong Yap-Seng, Collins Rory, Courtney Regina, Davies Gail, Delgado Graciela, Do Loi D, Doevendans Pieter A, Gansevoort Ron T, Gao Yu-Tang, Grammer Tanja B, Grarup Niels, Grewal Jagvir, Gu Dongfeng, Wander Gurpreet S, Hartikainen Anna-Liisa, Hazen Stanley L, He Jing, Heng Chew-Kiat, Hixson James E, Hofman Albert, Hsu Chris, Huang Wei, Husemoen Lise L N, Hwang Joo-Yeon, Ichihara Sahoko, Igase Michiya, Isono Masato, Justesen Johanne M, Katsuya Tomohiro, Kibriya Muhammad G, Kim Young Jin, Kishimoto Miyako, Koh Woon-Puay, Kohara Katsuhiko, Kumari Meena, Kwek Kenneth, Lee Nanette R, Lee Jeannette, Liao Jiemin, Lieb Wolfgang, Liewald David C M, Matsubara Tatsuaki, Matsushita Yumi, Meitinger Thomas, Mihailov Evelin, Milani Lili, Mills Rebecca, Mononen Nina, Müller-Nurasyid Martina, Nabika Toru, Nakashima Eitaro, Ng Hong Kiat, Nikus Kjell, Nutile Teresa, Ohkubo Takayoshi, Ohnaka Keizo, Parish Sarah, Paternoster Lavinia, Peng Hao, Peters Annette, Pham Son T, Pinidiyapathirage Mohitha J, Rahman Mahfuzar, Rakugi Hiromi, Rolandsson Olov, Ann Rozario Michelle, Ruggiero Daniela, Sala Cinzia F, Sarju Ralhan, Shimokawa Kazuro, Snieder Harold, Sparsø Thomas, Spiering Wilko, Starr John M, Stott David J, Stram Daniel O, Sugiyama Takao, Szymczak Silke, Tang W H Wilson, Tong Lin, Trompet Stella, Turjanmaa Väinö, Ueshima Hirotsugu, Uitterlinden André G, Umemura Satoshi, Vaarasmaki Marja, van Dam Rob M, van Gilst Wiek H, van Veldhuisen Dirk J, Viikari Jorma S, Waldenberger Melanie, Wang Yiqin, Wang Aili, Wilson Rory, Wong Tien-Yin, Xiang Yong-Bing, Yamaguchi Shuhei, Ye Xingwang, Young Robin D, Young Terri L, Yuan Jian-Min, Zhou Xueya, Asselbergs Folkert W, Ciullo Marina, Clarke Robert, Deloukas Panos, Franke Andre, Franks Paul W, Franks Steve, Friedlander Yechiel, Gross Myron D, Guo Zhirong, Hansen Torben, Jarvelin Marjo-Riitta, Jørgensen Torben, Jukema J Wouter, Kähönen Mika, Kajio Hiroshi, Kivimaki Mika, Lee Jong-Young, Lehtimäki Terho, Linneberg Allan, Miki Tetsuro, Pedersen Oluf, Samani Nilesh J, Sørensen Thorkild I A, Takayanagi Ryoichi, Toniolo Daniela, Ahsan Habibul, Allayee Hooman, Chen Yuan-Tsong, Danesh John, Deary Ian J, Franco Oscar H, Franke Lude, Heijman Bastiaan T, Holbrook Joanna D, Isaacs Aaron, Kim Bong-Jo, Lin Xu, Liu Jianjun, März Winfried, Metspalu Andres, Mohlke Karen L, Sanghera Dharambir K, Shu Xiao-Ou, van Meurs Joyce B J, Vithana Eranga, Wickremasinghe Ananda R, Wijmenga Cisca, Wolffenbuttel Bruce H W, Yokota Mitsuhiro, Zheng Wei, Zhu Dingliang, Vineis Paolo, Kyrtopoulos Soterios A, Kleinjans Jos C S, McCarthy Mark I, Soong Richie, Gieger Christian, Scott James, Teo Yik-Ying, He Jiang, Elliott Paul, Tai E Shyong, van der Harst Pim, Kooner Jaspal S, Chambers John C
机构信息
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.
出版信息
Nat Genet. 2015 Nov;47(11):1282-1293. doi: 10.1038/ng.3405. Epub 2015 Sep 21.
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.
我们对多达320251名东亚、欧洲和南亚血统个体的血压表型进行了跨血统全基因组关联和重复研究。我们发现12个新位点的基因变异与血压相关（P = 3.9 × 10⁻¹¹至5.0 × 10⁻²¹）。前导血压单核苷酸多态性（SNP）在多个附近的CpG位点与DNA甲基化的关联中富集，这表明在一些已确定的位点，DNA甲基化可能处于连接序列变异与血压的调控途径上。这12个新位点的前导SNP指向参与血管平滑肌（胰岛素样生长因子结合蛋白3、钾通道亚家族K成员3、磷酸二酯酶3A和PR结构域蛋白6）和肾脏（ARHGAP24、OSR1、溶质载体家族22成员7和TBX2）功能的基因。新的和已知的基因变异可预测左心室质量增加、N末端脑钠肽前体（NT-proBNP）循环水平升高以及心血管和全因死亡率增加（P = 0.04至8.6 × 10⁻⁶）。我们的结果为DNA甲基化在血压调节中的作用提供了新证据。
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