Genome-wide analysis in over 1 million individuals reveals over 2,000 independent genetic signals for blood pressure
Authors: Warren Helen , Edwards Todd , Vaez Ahmad , Keaton Jacob , Kamali Zoha , Xie Tian , Ani Alireza , Evangelou Evangelos , Hellwege Jacklyn , Yengo Loïc , Young William , Traylor Matthew , Giri Ayush , Visscher Peter , Chasman Daniel , Morris Andrew , Caulfield Mark , Hwang Shih-Jen , Kooner Jaspal , Conen David , Attia John , Morrison Alanna , Loos Ruth , Kristiansson Kati , Schmidt Reinhold , Hicks Andrew , Pramstaller Peter , Nelson Christopher , Samani Nilesh , Risch Lorenz , Gyllensten Ulf , Melander Olle , Riese Harriëtte , Wilson James , Campbell Harry , Psaty Bruce , Lu Yingchang , Rotter Jerome , Guo Xiuqing , Rice Kenneth , Vollenweider Peter , Sundstrom Johan , Langenberg Claudia , Tobin Martin , Giedraitis Vilmantas , Luan Jian'an , Tuomilehto Jaakko , Kutalik Zoltan , Ripatti Samuli , Salomaa Veikko , Girotto Giorgia , Trompet Stella , Jukema J Wouter , Harst Pim van der , Ridker Paul , Giulianini Franco , Vitart Veronique , Goel Anuj , Watkins Hugh , Harris Sarah , Deary Ian , Most Peter van der , Oldehinkel Albertine , Keavney Bernard , Hayward Caroline , Campbell Archie , Boehnke Michael , Scott Laura , Boutin Thibaud , Mamasoula Chrysovalanto , Jarvelin Marjo-Riitta , Peters Annette , Gieger Christian , Lakatta Edward , Cucca Francesco , Hui Jennie , Knekt Paul , Enroth Stefan , de Borst Martin , Polasek Ozren , Concas Maria Pina , Catamo Eulalia , Cocca Massimiliano , Li-Gao Ruifang , Hofer Edith , Schmidt Helena , Spedicati Beatrice , Waldenberger Melanie , Strachan David , Laan Maris , Teumer Alexander , Dörr Marcus , Gudnason Vilmundur , Cook James , Ruggiero Daniela , Kolcic Ivana , Boerwinkle Eric , Traglia Michela , Lehtimäki Terho , Raitakari Olli , Johnson Andrew , Newton-Cheh Christopher , Brown Morris , Dominiczak Anna , Sever Peter , Poulter Neil , Chambers John , Elosua Roberto , Siscovick David , Esko Tōnu , Metspalu Andres , Strawbridge Rona , Laakso Markku , Hamsten Anders , Hottenga Jouke-Jan , de Geus Eco , Morris Andrew , Palmer Colin , Nolte Ilja , Milaneschi Yuri , Marten Jonathan , Wright Alan , Zeggini Eleftheria , Howson Joanna , O'Donnell Christopher , Spector Tim , Nalls Mike , Simonsick Eleanor , Liu Yongmei , Duijn Cornelia van , Butterworth Adam , Danesh John , Menni Cristina , Wareham Nick , Khaw Kay , Denny Joshua , Levy Daniel , Munroe Patricia , Snieder Harold 
Published: March 2022

Abstract

Hypertension is a leading cause of premature death affecting more than a billion individuals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent individuals). We identified 2,103 independent genetic signals (P < 5x10− 8) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10− 73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P = 9.71×10− 33) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10− 22). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.