Trans-ethnic genome-wide association study identifies 15 new genetic loci influencing blood pressure traits, and implicates a role for DNA methylation: the International Genetics of Blood Pressure (iGEN-BP) Study. M. Loh1, F. Takeuchi2, N. Verweij3, X. Wang4, W. Zhang1,5, International Genetics of Blood Pressure Study 1) Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom; 2) Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; 3) University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands; 4) Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; 5) Ealing Hospital NHS Trust, Middlesex, UK.

   High blood pressure (BP) is a major risk factor for myocardial infarction, stroke and chronic kidney disease. Genome-wide association (GWA) studies have identified 50 genetic loci influencing BP in predominantly European populations. However the mechanisms linking the identified loci to BP phenotypes remain largely unknown. We carried out a trans-ethnic GWA and replication study of 5 BP phenotypes (systolic BP, diastolic BP, pulse pressure, mean arterial pressure and hypertension) amongst up to 313,449 individuals of East Asian, European and South Asian ancestry, with imputation of 2.1M HapMap2 SNPs. We then studied DNA methylation at the identified loci to investigate potential DNA regulatory mechanisms. We identify and replicate 38 loci at P<10-9, of which 15 are novel (P=7.5x10-10 to P=2.5x10-15) There was little evidence for heterogeneity of effect between the ethnic groups in either the GWA or replication data. The sentinel SNPs are enriched for variants associated with adiposity, type 2 diabetes, coronary heart disease, and kidney function in published GWA studies (P=2.5x10-3 to 1.6x10-10). A weighted genetic risk score also predicts increased left ventricular mass, circulating levels of NT-proBNP, cardiovascular and all-cause mortality (P=0.05 to 1.1x10-20). Thirteen of the sentinel SNPs are strongly associated with methylation of nearby CpG sites (P=10-6 to 10-300). Mendelian randomisation experiments implicate a role for methylation mediating the relationship between the DNA sequence variation and BP at the newly identified loci. At five loci the CpG sites are associated with expression of their nearest gene (P=10-4 to 10-14). The sentinel SNPs and leading CpG sites point to genes involved in vascular (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7, TBX2) structure and function. Our results identify 15 novel loci influencing BP, and provide the first evidence for DNA methylation as a potential mediator of the relationship between DNA sequence variation and BP phenotypes. Our findings provide the rationale for functional studies to evaluate DNA methylation as a potential therapeutic target in cardiovascular risk reduction.

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