Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Chunyu Liu, Aldi T. Kraja, Jennifer A. Smith, Jennifer A. Brody, Nora Franceschini, Joshua C. Bis, Kenneth Rice, Alanna C. Morrison, Yingchang Lu, Stefan Weiss, Xiuqing Guo, Walter Palmas, Lisa W. Martin, Yii Der Ida Chen, Praveen Surendran, Fotios Drenos, James P. Cook, Paul L. Auer, Audrey Y. Chu, Ayush GiriWei Zhao, Johanna Jakobsdottir, Li An Lin, Jeanette M. Stafford, Najaf Amin, Hao Mei, Jie Yao, Arend Voorman, Martin G. Larson, Megan L. Grove, Albert V. Smith, Shih Jen Hwang, Han Chen, Tianxiao Huan, Gulum Kosova, Nathan O. Stitziel, Sekar Kathiresan, Nilesh Samani, Heribert Schunkert, Panos Deloukas, Man Li, Christian Fuchsberger, Cristian Pattaro, Mathias Gorski, Charles Kooperberg, George J. Papanicolaou, Jacques E. Rossouw, Jessica D. Faul, Sharon L.R. Kardia, Claude Bouchard, Leslie J. Raffel, André G. Uitterlinden, Oscar H. Franco, Ramachandran S. Vasan, Christopher J. O'Donnell, Kent D. Taylor, Kiang Liu, Erwin P. Bottinger, Omri Gottesman, E. Warwick Daw, Franco Giulianini, Santhi Ganesh, Elias Salfati, Tamara B. Harris, Lenore J. Launer, Marcus Dörr, Stephan B. Felix, Rainer Rettig, Henry Völzke, Eric Kim, Wen Jane Lee, I. Te Lee, Wayne H.H. Sheu, Krystal S. Tsosie, Digna R.Velez Edwards, Yongmei Liu, Adolfo Correa, David R. Weir, Uwe Völker, Paul M. Ridker, Eric Boerwinkle, Vilmundur Gudnason, Alexander P. Reiner, Cornelia M. Van Duijn, Ingrid B. Borecki, Todd L. Edwards, Aravinda Chakravarti, Jerome I. Rotter, Bruce M. Psaty, Ruth J.F. Loos, Myriam Fornage, Georg B. Ehret, Christopher Newton-Cheh, Daniel Levy, Daniel I. Chasman

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1162-1170
Number of pages9
JournalNature genetics
Volume48
Issue number10
DOIs
StatePublished - Oct 1 2016

ASJC Scopus subject areas

  • Genetics

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    Liu, C., Kraja, A. T., Smith, J. A., Brody, J. A., Franceschini, N., Bis, J. C., Rice, K., Morrison, A. C., Lu, Y., Weiss, S., Guo, X., Palmas, W., Martin, L. W., Chen, Y. D. I., Surendran, P., Drenos, F., Cook, J. P., Auer, P. L., Chu, A. Y., ... Chasman, D. I. (2016). Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nature genetics, 48(10), 1162-1170. https://doi.org/10.1038/ng.3660