Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Lifelines Cohort Study, EPIC-CVD, EPIC-InterAct, Understanding Society Scientific Group, Million Veteran Program

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Abstract

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Original languageEnglish (US)
Pages (from-to)1314-1332
Number of pages19
JournalNature Genetics
Volume52
Issue number12
DOIs
StatePublished - Dec 2020

Bibliographical note

Funding Information:
P. Surendran is supported by a Rutherford Fund Fellowship from the Medical Research Council (grant no. MR/S003746/1). N.L. is supported by the Foundation “De Drie Lichten’ in the Netherlands and the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (CVON2012-10 PREDICT and CVON2018-30 PREDICT2). S. Karthikeyan and B.P. are funded by a BHF Programme Grant (RG/18/13/33946). J.N.H. was supported by the Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) Training Program (T32CA160056, PI X.-O.S.). N.F. is supported by the National Institute of Health awards HL140385, MD012765 and DK117445. E.Y.-D. was funded by the Isaac Newton Trust/Wellcome Trust ISSF/ University of Cambridge Joint Research Grants Scheme. R.C. is funded by a Medical Research Council-Newton Project Grant to study genetic risk factors of cardiovascular disease among Southeast Asians and a UK Research and Innovation-Global Challenges Research Fund Project Grant (CAPABLE) to study risk factors of non-communicable diseases in Bangladesh. F.W.A. is supported by UCL Hospitals NIHR Biomedical Research Centre. P.D. was supported by the British Heart Foundation (BHF) grant RG/14/5/30893. R.J.F.L. is funded by grants R01DK110113, U01HG007417, R01DK101855 and R01DK107786. C.H. is supported by MRC University Unit Programme grants MC_UU_00007/10 (QTL in Health and Disease) and MC_PC_ U127592696. M.I.M* was a Wellcome Senior Investigator (098381; 212259) and an NIHR Senior Investigator (NF-SI-0617-10090). The research was supported by the NIHR Oxford Biomedical Research Centre (BRC) and by the Wellcome Trust (090532, 106130, 098381, 203141 and 212259). The views expressed by C.Y., S.H., J.R. and G.J.P. are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. T.F.* is supported by the NIHR Biomedical Research Centre in Oxford. M.J. is supported by PrevMetSyn/SALVE, H2020 DynaHEALTH action (grant agreement 633595), EU H2020-HCO-2004 iHEALTH Action (grant agreement 643774). K.-H.H. is supported by PrevMetSyn/SALVE, H2020 DynaHEALTH action (grant agreement 633595) and EU H2020-HCO-2004 iHEALTH Action (grant agreement 643774). N.S. is supported by the British Heart Foundation Research Excellence Award (RE/18/6/34217). J.P. is supported by a UKRI Innovation Fellowship at Health Data Research UK. N.F. is supported by NIH awards R01-DK117445, R01-MD012765 and R21-HL140385. G.D.S., T.R.G. and C.L.R. work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1, 4 & 5). S.T. holds a Junior 1 Clinical Research Scholar award from the Fonds de Recherche du Québec-Santé (FRQS). M.T. is supported by the BHF (PG/17/35/33001 and PG/19/16/34270) and Kidney Research UK (RP_017_20180302). V.S.R. is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. J.D.* holds a British Heart Foundation Professorship and a National Institute for Health Research Senior Investigator Award. C.M.L.* is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, by Widenlife and the National Institutes of Health (5P50HD028138-27). J.M.M.H.* was funded by the NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). *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. Full acknowledgements and full lists of consortia members are provided in the Supplementary Note.

Funding Information:
The following authors affiliated with deCODE genetics/Amgen are employed by the company: V.T., G. Thorleifsson, A.H., P. Sulem, G. Thorgeirsson, H. H, D.F.G., U.T. and K.S. B.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. J.D. reports grants, personal fees and nonfinancial support from Merck Sharp & Dohme; grants, personal fees and nonfinancial support from Novartis; grants from Pfizer; and grants from AstraZeneca outside the submitted work. J.D. sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING) member, London (since 2013); the MRC High Throughput Science ‘Omics Panel Member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the Astra Zeneca Genomics Advisory Board (2018). A.B. reports grants outside of this work from AstraZeneca, Biogen, Merck, Novartis and Pfizer and personal fees from Novartis. V.S. has participated in a conference trip sponsored by Novo Nordisk and received an honorarium for participating in an advisor board meeting, outside the present study. V.S. also has ongoing research collaboration with Bayer, outside the present study. The spouse of C.J.W. works at Regeneron. N.S. is partially supported by Fundação para a Ciência e Tecnologia, Portugal (grant ref. UID/MAT/00006/2013 and UID/MAT/00006/2019). M.E.J. has received research grants from AMGEN, Sanofi Aventis, Astra Zeneca and Boehringer Ingelheim. M.E.J. holds shares in Novo Nordisk. J.T. has received honoraria from AstraZeneca, Eli Lilly and Merck, and research funding from Bayer, Boehringer Ingelheim and Merck, and is a stock owner of Orion Pharma. D.O.M.-K. is a part-time clinical research consultant for Metabolon. M.I.M. has served on advisory panels for Pfizer, Novo Nordisk, Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. D.S.P. became a full-time employee of AstraZeneca during the revision of the manuscript. E.B.F. is an employee of and owns stock in Pfizer. M.J.C. is Chief Scientist for Genomics England, a UK Government company. J.M.M.H. became a full-time employee of Novo Nordisk, and I.N. became a full-time employee of Gilead during revision of the manuscript.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

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