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 N. Kelly; 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; Tonu 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; Ying Wu; Ron T. Gansevoort; Meena Kumari; Harold Snieder; Wiek H. van Gilst; Dirk J. van Veldhuisen; Folkert W. Asselbergs; Lude Franke; Cisca Wijmenga; Bruce H. W. Wolffenbuttel; Pim van der Harst; BIOS Consortium; CARDIo GRAMplusCD; Lifelines Cohort Study; InterAct Consortium

doi:10.1038/ng.3405

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 N. Kelly, 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, Tonu 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, Ying Wu, Ron T. Gansevoort, Meena Kumari, Harold Snieder, Wiek H. van Gilst, Dirk J. van Veldhuisen, Folkert W. Asselbergs, Lude Franke, Cisca Wijmenga, Bruce H. W. Wolffenbuttel, Pim van der Harst, BIOS Consortium, CARDIo GRAMplusCD, Lifelines Cohort Study, InterAct Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

166 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 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.

Original language	English
Pages (from-to)	1282-1293.e2
Number of pages	14
Journal	Nature Genetics
Volume	47
Issue number	11
DOIs	https://doi.org/10.1038/ng.3405
Publication status	Published - Nov-2015

Keywords

PULMONARY ARTERIAL-HYPERTENSION
CENTRIC ARRAY
RISK-FACTORS
CARDIOVASCULAR-DISEASE
VARIANTS
REGIONS
KIDNEY
TISSUE
METAANALYSIS
INDIVIDUALS

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Kato, N., Loh, M., Takeuchi, F., Verweij, N., Wang, X., Zhang, W., Kelly, T. N., Saleheen, D., Lehne, B., Leach, I. M., Drong, A. W., Abbott, J., Wahl, S., Tan, S-T., Scott, W. R., Campanella, G., Chadeau-Hyam, M., Afzal, U., Ahluwalia, T. S., ... InterAct Consortium (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), 1282-1293.e2. https://doi.org/10.1038/ng.3405

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, 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 ; Wu, Ying ; Gansevoort, Ron T. ; Kumari, Meena ; Snieder, Harold ; van Gilst, Wiek H. ; van Veldhuisen, Dirk J. ; Asselbergs, Folkert W. ; Franke, Lude ; Wijmenga, Cisca ; Wolffenbuttel, Bruce H. W. ; van der Harst, Pim ; BIOS Consortium ; CARDIo GRAMplusCD ; Lifelines Cohort Study ; InterAct Consortium. / Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. In: Nature Genetics. 2015 ; Vol. 47, No. 11. pp. 1282-1293.e2.

@article{603dc7aa565148bbb1ecf794caa73edd,

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

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 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.",

keywords = "PULMONARY ARTERIAL-HYPERTENSION, CENTRIC ARRAY, RISK-FACTORS, CARDIOVASCULAR-DISEASE, VARIANTS, REGIONS, KIDNEY, TISSUE, METAANALYSIS, INDIVIDUALS",

author = "Norihiro Kato and Marie Loh and Fumihiko Takeuchi and Niek Verweij and Xu Wang and Weihua Zhang and Kelly, {Tanika N.} and Danish Saleheen and Benjamin Lehne and Leach, {Irene Mateo} and Drong, {Alexander W.} and James Abbott and Simone Wahl and Sian-Tsung Tan and Scott, {William R.} and Gianluca Campanella and Marc Chadeau-Hyam and Uzma Afzal and Ahluwalia, {Tarunveer S.} and Bonder, {Marc Jan} and Peng Chen and Abbas Dehghan and Edwards, {Todd L.} and Tonu Esko and Go, {Min Jin} and Harris, {Sarah E.} and Jaana Hartiala and Silva Kasela and Anuradhani Kasturiratne and Chiea-Chuen Khor and Kleber, {Marcus E.} and Huaixing Li and Mok, {Zuan Yu} and Masahiro Nakatochi and Sapari, {Nur Sabrina} and Richa Saxena and Stewart, {Alexandre F. R.} and Lisette Stolk and Yasuharu Tabara and Ying Wu and Gansevoort, {Ron T.} and Meena Kumari and Harold Snieder and {van Gilst}, {Wiek H.} and {van Veldhuisen}, {Dirk J.} and Asselbergs, {Folkert W.} and Lude Franke and Cisca Wijmenga and Wolffenbuttel, {Bruce H. W.} and {van der Harst}, Pim and {BIOS Consortium} and {CARDIo GRAMplusCD} and {Lifelines Cohort Study} and {InterAct Consortium}",

year = "2015",

month = nov,

doi = "10.1038/ng.3405",

language = "English",

volume = "47",

pages = "1282--1293.e2",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

}

Kato, N, Loh, M, Takeuchi, F, Verweij, N, Wang, X, Zhang, W, Kelly, TN, Saleheen, D, Lehne, B, Leach, IM, Drong, AW, Abbott, J, Wahl, S, Tan, S-T, Scott, WR, Campanella, G, Chadeau-Hyam, M, Afzal, U, Ahluwalia, TS, Bonder, MJ, Chen, P, Dehghan, A, Edwards, TL, Esko, T, Go, MJ, Harris, SE, Hartiala, J, Kasela, S, Kasturiratne, A, Khor, C-C, Kleber, ME, Li, H, Mok, ZY, Nakatochi, M, Sapari, NS, Saxena, R, Stewart, AFR, Stolk, L, Tabara, Y, Wu, Y, Gansevoort, RT, Kumari, M, Snieder, H , van Gilst, WH , van Veldhuisen, DJ, Asselbergs, FW, Franke, L , Wijmenga, C , Wolffenbuttel, BHW , van der Harst, P, BIOS Consortium, CARDIo GRAMplusCD, Lifelines Cohort Study & InterAct Consortium 2015, 'Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation', Nature Genetics, vol. 47, no. 11, pp. 1282-1293.e2. https://doi.org/10.1038/ng.3405

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; 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, 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; Wu, Ying; Gansevoort, Ron T.; Kumari, Meena; Snieder, Harold ; van Gilst, Wiek H.; van Veldhuisen, Dirk J.; Asselbergs, Folkert W.; Franke, Lude ; Wijmenga, Cisca ; Wolffenbuttel, Bruce H. W.; van der Harst, Pim; BIOS Consortium; CARDIo GRAMplusCD; Lifelines Cohort Study; InterAct Consortium.

In: Nature Genetics, Vol. 47, No. 11, 11.2015, p. 1282-1293.e2.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

AU - Kato, Norihiro

AU - Loh, Marie

AU - Takeuchi, Fumihiko

AU - Verweij, Niek

AU - Wang, Xu

AU - Zhang, Weihua

AU - Kelly, Tanika N.

AU - Saleheen, Danish

AU - Lehne, Benjamin

AU - Leach, Irene Mateo

AU - Drong, Alexander W.

AU - Abbott, James

AU - Wahl, Simone

AU - Tan, Sian-Tsung

AU - Scott, William R.

AU - Campanella, Gianluca

AU - Chadeau-Hyam, Marc

AU - Afzal, Uzma

AU - Ahluwalia, Tarunveer S.

AU - Bonder, Marc Jan

AU - Chen, Peng

AU - Dehghan, Abbas

AU - Edwards, Todd L.

AU - Esko, Tonu

AU - Go, Min Jin

AU - Harris, Sarah E.

AU - Hartiala, Jaana

AU - Kasela, Silva

AU - Kasturiratne, Anuradhani

AU - Khor, Chiea-Chuen

AU - Kleber, Marcus E.

AU - Li, Huaixing

AU - Mok, Zuan Yu

AU - Nakatochi, Masahiro

AU - Sapari, Nur Sabrina

AU - Saxena, Richa

AU - Stewart, Alexandre F. R.

AU - Stolk, Lisette

AU - Tabara, Yasuharu

AU - Wu, Ying

AU - Gansevoort, Ron T.

AU - Kumari, Meena

AU - Snieder, Harold

AU - van Gilst, Wiek H.

AU - van Veldhuisen, Dirk J.

AU - Asselbergs, Folkert W.

AU - Franke, Lude

AU - Wijmenga, Cisca

AU - Wolffenbuttel, Bruce H. W.

AU - van der Harst, Pim

AU - BIOS Consortium

AU - CARDIo GRAMplusCD

AU - Lifelines Cohort Study

AU - InterAct Consortium

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

KW - PULMONARY ARTERIAL-HYPERTENSION

KW - CENTRIC ARRAY

KW - RISK-FACTORS

KW - CARDIOVASCULAR-DISEASE

KW - VARIANTS

KW - REGIONS

KW - KIDNEY

KW - TISSUE

KW - METAANALYSIS

KW - INDIVIDUALS

U2 - 10.1038/ng.3405

DO - 10.1038/ng.3405

M3 - Article

C2 - 26390057

VL - 47

SP - 1282-1293.e2

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 11

ER -