Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Jacob M. Keaton; Zoha Kamali; Tian Xie; Jouke Jan Hottenga; Eco de Geus; Yuri Milaneschi; Patricia B. Munroe; Harold Snieder; Helen R. Warren; Million Veteran Program; LifeLines Cohort Study; CHARGE Consortium; ICBP Consortium

doi:10.1038/s41588-024-01714-w

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Jacob M. Keaton, Zoha Kamali, Tian Xie, Jouke Jan Hottenga, Eco de Geus, Yuri Milaneschi, Patricia B. Munroe, Harold Snieder, Helen R. Warren, Million Veteran Program, LifeLines Cohort Study, CHARGE Consortium, ICBP Consortium

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Original language	English
Pages (from-to)	778-791
Number of pages	14
Journal	Nature genetics
Volume	56
Issue number	5
DOIs	https://doi.org/10.1038/s41588-024-01714-w
Publication status	Published - 1 May 2024

Bibliographical note

Publisher Copyright:
© 2024. The Author(s).

Funding

J.N.H. is supported by the National Institutes of Health (grant no. K12HD04348; principal investigator K. E. Hartmann). T.E. and A.M. were supported by the Council of Europe (grant no. 2014-2020.4.01.15-0012) and Estonian Research Council (grant no. PRG1291). Z.K. is supported by Isfahan University of Medical Sciences (3400581) and Iran\u2019s National Elites Foundation (grant no. ISF140100108). J.N.D. holds a British Heart Foundation Professorship and a National Institute for Health Research Senior Investigator Award. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Cohort support was provided by the Million Veteran Program (MVP) VA Award BX004821 (to P.W.F.W. and K.C.). Individual cohort acknowledgements are provided in the Supplementary Notes. We dedicate this paper to the memory of Evangelos Evangelou (the first author of our previous BP-GWAS paper5), who sadly passed away in July 2023. J.N.H. is supported by the National Institutes of Health (grant no. K12HD04348; principal investigator K. E. Hartmann). T.E. and A.M. were supported by the Council of Europe (grant no. 2014-2020.4.01.15-0012) and Estonian Research Council (grant no. PRG1291). Z.K. is supported by Isfahan University of Medical Sciences (3400581) and Iran\u2019s National Elites Foundation (grant no. ISF140100108). J.N.D. holds a British Heart Foundation Professorship and a National Institute for Health Research Senior Investigator Award. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Cohort support was provided by the Million Veteran Program (MVP) VA Award BX004821 (to P.W.F.W. and K.C.). Individual cohort acknowledgements are provided in the . We dedicate this paper to the memory of Evangelos Evangelou (the first author of our previous BP-GWAS paper), who sadly passed away in July 2023.

Funders	Funder number
National Institute on Handicapped Research
Institute for Mental Health Research
British Heart Foundation
Eesti Teadusagentuur	PRG1291
Isfahan University of Medical Sciences	3400581
Council of Europe	2014-2020.4.01.15-0012
National Institutes of Health	K12HD04348
National Foundation of Elites	ISF140100108
Million Veteran Program	BX004821

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Keaton, J. M., Kamali, Z., Xie, T., Hottenga, J. J., de Geus, E., Milaneschi, Y., Munroe, P. B., Snieder, H., Warren, H. R., Million Veteran Program, LifeLines Cohort Study, CHARGE Consortium, & ICBP Consortium (2024). Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits. Nature genetics, 56(5), 778-791. https://doi.org/10.1038/s41588-024-01714-w

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abstract = "Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.",

author = "Keaton, {Jacob M.} and Zoha Kamali and Tian Xie and Ahmad Vaez and Ariel Williams and Goleva, {Slavina B.} and Alireza Ani and Evangelos Evangelou and Hellwege, {Jacklyn N.} and Loic Yengo and Young, {William J.} and Matthew Traylor and Ayush Giri and Zhili Zheng and Jian Zeng and Chasman, {Daniel I.} and Morris, {Andrew P.} and Caulfield, {Mark J.} and Hwang, {Shih Jen} and Kooner, {Jaspal S.} and David Conen and Attia, {John R.} and Morrison, {Alanna C.} and Loos, {Ruth J.F.} and Kati Kristiansson and Reinhold Schmidt and Hicks, {Andrew A.} and Pramstaller, {Peter P.} and Nelson, {Christopher P.} and Samani, {Nilesh J.} and Lorenz Risch and Ulf Gyllensten and Olle Melander and Harriette Riese and Wilson, {James F.} and Harry Campbell and Rich, {Stephen S.} and Psaty, {Bruce M.} and Yingchang Lu and Rotter, {Jerome I.} and Xiuqing Guo and Rice, {Kenneth M.} and Peter Vollenweider and Johan Sundstr{\"o}m and Claudia Langenberg and Tobin, {Martin D.} and Vilmantas Giedraitis and Jian'an Luan and Jaakko Tuomilehto and Zoltan Kutalik and Samuli Ripatti and Veikko Salomaa and Giorgia Girotto and Stella Trompet and Jukema, {J. Wouter} and {van der Harst}, Pim and Ridker, {Paul M.} and Franco Giulianini and Veronique Vitart and Anuj Goel and Hugh Watkins and Harris, {Sarah E.} and Deary, {Ian J.} and {van der Most}, {Peter J.} and Oldehinkel, {Albertine J.} and Keavney, {Bernard D.} and Caroline Hayward and Archie Campbell and Michael Boehnke and Scott, {Laura J.} and Thibaud Boutin and Chrysovalanto Mamasoula and J{\"a}rvelin, {Marjo Riitta} and Annette Peters and Christian Gieger and Lakatta, {Edward G.} and Francesco Cucca and Jennie Hui and Paul Knekt and Stefan Enroth and {De Borst}, {Martin H.} and Ozren Pola{\v s}ek and Concas, {Maria Pina} and Eulalia Catamo and Massimiliano Cocca and Ruifang Li-Gao and Edith Hofer and Helena Schmidt and Beatrice Spedicati and Melanie Waldenberger and Strachan, {David P.} and Maris Laan and Alexander Teumer and Marcus D{\"o}rr and Vilmundur Gudnason and Cook, {James P.} and Daniela Ruggiero and Ivana Kolcic and Eric Boerwinkle and Michela Traglia and Terho Lehtim{\"a}ki and Raitakari, {Olli T.} and Johnson, {Andrew D.} and Christopher Newton-Cheh and Brown, {Morris J.} and Dominiczak, {Anna F.} and Sever, {Peter J.} and Neil Poulter and Chambers, {John C.} and Roberto Elosua and David Siscovick and T{\~o}nu Esko and Andres Metspalu and Strawbridge, {Rona J.} and Markku Laakso and Anders Hamsten and Hottenga, {Jouke Jan} and {de Geus}, Eco and Morris, {Andrew D.} and Palmer, {Colin N.A.} and Nolte, {Ilja M.} and Yuri Milaneschi and Jonathan Marten and Alan Wright and Eleftheria Zeggini and Howson, {Joanna M.M.} and O'Donnell, {Christopher J.} and Tim Spector and Nalls, {Mike A.} and Simonsick, {Eleanor M.} and Yongmei Liu and {van Duijn}, {Cornelia M.} and Butterworth, {Adam S.} and Danesh, {John N.} and Cristina Menni and Wareham, {Nicholas J.} and Khaw, {Kay Tee} and Sun, {Yan V.} and Wilson, {Peter W.F.} and Kelly Cho and Visscher, {Peter M.} and Denny, {Joshua C.} and Daniel Levy and Edwards, {Todd L.} and Munroe, {Patricia B.} and Harold Snieder and Warren, {Helen R.} and {Million Veteran Program} and {LifeLines Cohort Study} and {CHARGE Consortium} and {ICBP Consortium}",

note = "Publisher Copyright: {\textcopyright} 2024. The Author(s).",

year = "2024",

month = may,

day = "1",

doi = "10.1038/s41588-024-01714-w",

language = "English",

volume = "56",

pages = "778--791",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

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Keaton, JM, Kamali, Z, Xie, T, Hottenga, JJ , de Geus, E, Milaneschi, Y, Munroe, PB, Snieder, H, Warren, HR, Million Veteran Program, LifeLines Cohort Study, CHARGE Consortium & ICBP Consortium 2024, 'Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits', Nature genetics, vol. 56, no. 5, pp. 778-791. https://doi.org/10.1038/s41588-024-01714-w

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AU - Chambers, John C.

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AU - Edwards, Todd L.

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AU - Snieder, Harold

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N2 - Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

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Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

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