Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.
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., Yu Mok Z., Nakatochi M., Sapari NS., Saxena R., Stewart AFR., Stolk L., Tabara Y., Teh AL., Wu Y., Wu J-Y., Zhang Y., Aits I., Da Silva Couto Alves A., Das S., Dorajoo R., Hopewell JC., Kim YK., Koivula RW., Luan J., Lyytikäinen L-P., Nguyen QN., Pereira MA., Postmus I., Raitakari OT., Scannell Bryan M., Scott RA., Sorice R., Tragante V., Traglia M., White J., Yamamoto K., Zhang Y., Adair LS., Ahmed A., Akiyama K., Asif R., Aung T., Barroso I., Bjonnes A., Braun TR., Cai H., Chang L-C., Chen C-H., Cheng C-Y., Chong Y-S., Collins R., Courtney R., Davies G., Delgado G., Do LD., Doevendans PA., Gansevoort RT., Gao Y-T., Grammer TB., Grarup N., Grewal J., Gu D., Wander GS., Hartikainen A-L., Hazen SL., He J., Heng C-K., Hixson JE., Hofman A., Hsu C., Huang W., Husemoen LLN., Hwang J-Y., Ichihara S., Igase M., Isono M., Justesen JM., Katsuya T., Kibriya MG., Kim YJ., Kishimoto M., Koh W-P., Kohara K., Kumari M., Kwek K., Lee NR., Lee J., Liao J., Lieb W., Liewald DCM., Matsubara T., Matsushita Y., Meitinger T., Mihailov E., Milani L., Mills R., Mononen N., Müller-Nurasyid M., Nabika T., Nakashima E., Ng HK., Nikus K., Nutile T., Ohkubo T., Ohnaka K., Parish S., Paternoster L., Peng H., Peters A., Pham ST., Pinidiyapathirage MJ., Rahman M., Rakugi H., Rolandsson O., Ann Rozario M., Ruggiero D., Sala CF., Sarju R., Shimokawa K., Snieder H., Sparsø T., Spiering W., Starr JM., Stott DJ., Stram DO., Sugiyama T., Szymczak S., Tang WHW., Tong L., Trompet S., Turjanmaa V., Ueshima H., Uitterlinden AG., Umemura S., Vaarasmaki M., van Dam RM., van Gilst WH., van Veldhuisen DJ., Viikari JS., Waldenberger M., Wang Y., Wang A., Wilson R., Wong T-Y., Xiang Y-B., Yamaguchi S., Ye X., Young RD., Young TL., Yuan J-M., Zhou X., Asselbergs FW., Ciullo M., Clarke R., Deloukas P., Franke A., Franks PW., Franks S., Friedlander Y., Gross MD., Guo Z., Hansen T., Jarvelin M-R., Jørgensen T., Jukema JW., Kähönen M., Kajio H., Kivimaki M., Lee J-Y., Lehtimäki T., Linneberg A., Miki T., Pedersen O., Samani NJ., Sørensen TIA., Takayanagi R., Toniolo D., BIOS-consortium None., CARDIo GRAMplusCD None., LifeLines Cohort Study None., InterAct Consortium None., Ahsan H., Allayee H., Chen Y-T., Danesh J., Deary IJ., Franco OH., Franke L., Heijman BT., Holbrook JD., Isaacs A., Kim B-J., Lin X., Liu J., März W., Metspalu A., Mohlke KL., Sanghera DK., Shu X-O., van Meurs JBJ., Vithana E., Wickremasinghe AR., Wijmenga C., Wolffenbuttel BHW., Yokota M., Zheng W., Zhu D., Vineis P., Kyrtopoulos SA., Kleinjans JCS., McCarthy MI., Soong R., Gieger C., Scott J., Teo Y-Y., He J., Elliott P., Tai ES., van der Harst P., Kooner JS., Chambers JC.
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.