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 journalArticleAcademicpeer-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 languageEnglish
Pages (from-to)1282-1293.e2
Number of pages14
JournalNature Genetics
Volume47
Issue number11
DOIs
Publication statusPublished - Nov-2015

Keywords

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

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