Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.
Liu C., Kraja AT., Smith JA., Brody JA., Franceschini N., Bis JC., Rice K., Morrison AC., Lu Y., Weiss S., Guo X., Palmas W., Martin LW., Chen Y-DI., Surendran P., Drenos F., Cook JP., Auer PL., Chu AY., Giri A., Zhao W., Jakobsdottir J., Lin L-A., Stafford JM., Amin N., Mei H., Yao J., Voorman A., CHD Exome+ Consortium None., ExomeBP Consortium None., GoT2DGenes Consortium None., T2D-GENES Consortium None., Larson MG., Grove ML., Smith AV., Hwang S-J., Chen H., Huan T., Kosova G., Stitziel NO., Kathiresan S., Samani N., Schunkert H., Deloukas P., Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia None., Li M., Fuchsberger C., Pattaro C., Gorski M., CKDGen Consortium None., Kooperberg C., Papanicolaou GJ., Rossouw JE., Faul JD., Kardia SLR., Bouchard C., Raffel LJ., Uitterlinden AG., Franco OH., Vasan RS., O'Donnell CJ., Taylor KD., Liu K., Bottinger EP., Gottesman O., Daw EW., Giulianini F., Ganesh S., Salfati E., Harris TB., Launer LJ., Dörr M., Felix SB., Rettig R., Völzke H., Kim E., Lee W-J., Lee I-T., Sheu WH-H., Tsosie KS., Edwards DRV., Liu Y., Correa A., Weir DR., Völker U., Ridker PM., Boerwinkle E., Gudnason V., Reiner AP., van Duijn CM., Borecki IB., Edwards TL., Chakravarti A., Rotter JI., Psaty BM., Loos RJF., Fornage M., Ehret GB., Newton-Cheh C., Levy D., Chasman DI.
Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.