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

Kato, Norihiro; Loh, Marie; Takeuchi, Fumihiko; Verweij, Niek; Wang, Xu; Zhang, Weihua; Kelly, Tanika N.; Saleheen, Danish; Lehne, Benjamin; Mateo Leach, Irene; 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, Tonu; Go, Min Jin; Harris, Sarah E.; Hartiala, Jaana; Kasela, Silva; Kasturiratne, Anuradhani; Khor, Chiea-Chuen; Kleber, Marcus E.; Li, Huaixing; Mok, Zuan Yu; 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; Lyytikainen, 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, Ines; 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; Muller-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; Rozario, Michelle Ann; Ruggiero, Daniela; Sala, Cinzia F.; Sarju, Ralhan; Shimokawa, Kazuro; Snieder, Harold; Sparso, 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, Vaino; Ueshima, Hirotsugu; Uitterlinden, Andre 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; Jorgensen, Torben; Jukema, J. Wouter; Kahonen, Mika; Kajio, Hiroshi; Kivimaki, Mika; Lee, Jong-Young; Lehtimaki, Terho; Linneberg, Allan; Miki, Tetsuro; Pedersen, Oluf; Samani, Nilesh J.; Sorensen, Thorkild I. A.; Takayanagi, Ryoichi; Toniolo, Daniela; BIOS-consortium; GRAMplusCD, CARDIo; Study, LifeLines Cohort; Consortium, InterAct; 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; Marz, 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. (2015). Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nature Genetics, 47(11), 1282-93. PMCID: PMC4719169

Kato, Norihiro; Loh, Marie; Takeuchi, Fumihiko; Verweij, Niek; Wang, Xu; Zhang, Weihua; Kelly, Tanika N.; Saleheen, Danish; Lehne, Benjamin; Mateo Leach, Irene; 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, Tonu; Go, Min Jin; Harris, Sarah E.; Hartiala, Jaana; Kasela, Silva; Kasturiratne, Anuradhani; Khor, Chiea-Chuen; Kleber, Marcus E.; Li, Huaixing; Mok, Zuan Yu; 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; Lyytikainen, 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, Ines; 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; Muller-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; Rozario, Michelle Ann; Ruggiero, Daniela; Sala, Cinzia F.; Sarju, Ralhan; Shimokawa, Kazuro; Snieder, Harold; Sparso, 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, Vaino; Ueshima, Hirotsugu; Uitterlinden, Andre 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; Jorgensen, Torben; Jukema, J. Wouter; Kahonen, Mika; Kajio, Hiroshi; Kivimaki, Mika; Lee, Jong-Young; Lehtimaki, Terho; Linneberg, Allan; Miki, Tetsuro; Pedersen, Oluf; Samani, Nilesh J.; Sorensen, Thorkild I. A.; Takayanagi, Ryoichi; Toniolo, Daniela; BIOS-consortium; GRAMplusCD, CARDIo; Study, LifeLines Cohort; Consortium, InterAct; 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; Marz, 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. (2015). Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nature Genetics, 47(11), 1282-93. PMCID: PMC4719169

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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 x 10(-11) to 5.0 x 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 x 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.




JOUR



Kato, Norihiro
Loh, Marie
Takeuchi, Fumihiko
Verweij, Niek
Wang, Xu
Zhang, Weihua
Kelly, Tanika N.
Saleheen, Danish
Lehne, Benjamin
Mateo Leach, Irene
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, Tonu
Go, Min Jin
Harris, Sarah E.
Hartiala, Jaana
Kasela, Silva
Kasturiratne, Anuradhani
Khor, Chiea-Chuen
Kleber, Marcus E.
Li, Huaixing
Mok, Zuan Yu
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
Lyytikainen, 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, Ines
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
Muller-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
Rozario, Michelle Ann
Ruggiero, Daniela
Sala, Cinzia F.
Sarju, Ralhan
Shimokawa, Kazuro
Snieder, Harold
Sparso, 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, Vaino
Ueshima, Hirotsugu
Uitterlinden, Andre 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
Jorgensen, Torben
Jukema, J. Wouter
Kahonen, Mika
Kajio, Hiroshi
Kivimaki, Mika
Lee, Jong-Young
Lehtimaki, Terho
Linneberg, Allan
Miki, Tetsuro
Pedersen, Oluf
Samani, Nilesh J.
Sorensen, Thorkild I. A.
Takayanagi, Ryoichi
Toniolo, Daniela
BIOS-consortium
GRAMplusCD, CARDIo
Study, LifeLines Cohort
Consortium, InterAct
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
Marz, 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.



2015


Nature Genetics

47

11

1282-93


2015/09/22




1546-1718 (Electronic) 1061-4036 (Linking)

10.1038/ng.3405

PMC4719169

Ems66668

230