Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

A Publisher Correction to this article was published on 14 November 2018

This article has been updated

Abstract

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

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Fig. 1: Study design schematic for discovery and validation of loci.
Fig. 2: Manhattan plot showing the minimum P-value for the association across all blood pressure traits in the discovery stage excluding known and previously reported variants.
Fig. 3: Venn diagrams of novel locus results.
Fig. 4: Association of blood pressure loci with lifestyle traits.
Fig. 5: Association of blood pressure loci with other traits and diseases.
Fig. 6: Association of blood pressure loci with other traits and diseases.
Fig. 7: Relationship of deciles of the genetic risk score (GRS) based on all 901 loci with blood pressure, risk of hypertension and cardiovascular disease in UKB.
Fig. 8: Known and novel blood pressure associations in the TGFβ signaling pathway.

Data availability

The genetic and phenotypic UKB data are available upon application to the UK Biobank (https://www.ukbiobank.ac.uk). ICBP summary data can be accessed through request to the ICBP steering committee. Contact the corresponding authors to apply for access to the data. The UKB + ICBP summary GWAS discovery data can be accessed by request to the corresponding authors and will be available via LDHub (http://ldsc.broadinstitute.org/ldhub/). All replication data generated during this study are included in the published article. For example, association results of look-up variants from our replication analyses and the subsequent combined meta-analyses are contained within the Supplementary Tables.

Change history

  • 14 November 2018

    In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

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Acknowledgements

H.R.W. was funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Centre at Barts and The London School of Medicine and Dentistry. D.M.-A. is supported by the Medical Research Council (grant number MR/L01632X.1). B.M. holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. H.G. was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. C.P.C. was funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Center at Barts and The London School of Medicine and Dentistry. S. Thériault was supported by Canadian Institutes of Health Research; Université Laval (Quebec City, Canada). G.P. was supported by Canada Research Chair in Genetic and Molecular Epidemiology and CISCO Professorship in Integrated Health Biosystems. I. Karaman was supported by the EU PhenoMeNal project (Horizon 2020, 654241). C.P.K. is supported by grant U01DK102163 from the NIH-NIDDK and by resources from the Memphis VA Medical Center. S.D. was supported for this work by grants from the European Research Council (ERC), the EU Joint Programme – Neurodegenerative Disease Research (JPND) and the Agence Nationale de la Recherche (ANR). T. Boutin, J. Marten, V.V., A.F.W. and C.H. were supported by a core MRC grant to the MRCHGU QTL in Health and Disease research programme. M. Boehnke is supported by NIH grant R01-DK062370. H.W. and A. Goel acknowledge support of the Tripartite Immunometabolism Consortium (TrIC), Novo Nordisk Foundation (grant NNF15CC0018486). N.V. was supported by a Marie Sklodowska-Curie GF grant (661395) and ICIN-NHI. C. Menni is funded by the MRC AimHy (MR/M016560/1) project grant. M.A.N.’s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH. M. Brumat, M. Cocca, I.G., P.G., G.G., A. Morgan, A.R., D.V., C.M.B., C.F.S., M. Traglia and D.T. were supported by Italian Ministry of Health grant RF2010 to P.G. and RC2008 to P.G. D.I.B. is supported by the Royal Netherlands Academy of Science Professor Award (PAH/6635). J.C.C. is supported by the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017). C.P.C., P.B.M. and M.R.B. were funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Centre at Barts. T.F. is supported by the NIHR Biomedical Research Centre, Oxford. M.R. is the recipient of an award from China Scholarship Council (No. 2011632047). C.L. was supported by the Medical Research Council UK (G1000143, MC_UU_12015/1, MC_PC_13048 and MC_U106179471), Cancer Research UK (C864/A14136) and EU FP6 programme (LSHM_CT_2006_037197). G.B.E. is supported by the Swiss National Foundation SPUM project FN 33CM30-124087, Geneva University, and the Fondation pour Recherches Médicales, Genève. C.M.L.is supported by the Li Ka Shing Foundation; WT-SSI/John Fell funds; the NIHR Biomedical Research Centre, Oxford; Widenlife; and NIH (CRR00070 CR00.01). R.J.F.L. is supported by the NIH (R01DK110113, U01HG007417, R01DK101855 and R01DK107786). D.O.M.-K. is supported by the Dutch Science Organization (ZonMW-VENI Grant 916.14.023). M.M. was supported by the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. H.W. and M.F. acknowledge the support of the Wellcome Trust core award (090532/Z/09/Z) and the BHF Centre of Research Excellence (RE/13/1/30181). A. Goel and H.W. acknowledge the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. HEALTH-F2-2013-601456 (CVGenes@Target) and A. Goel the Wellcome Trust Institutional strategic support fund. L.R. was supported by Forschungs- und Förder-Stiftung INOVA, Liechtenstein. M. Tomaszewski is supported by British Heart Foundation (PG/17/35/33001). P. Sever is recipient of an NIHR Senior Investigator Award and is supported by the Biomedical Research Centre Award to Imperial College Healthcare NHS Trust. P.v.d.H. was supported by the ICIN-NHI and Marie Sklodowska-Curie GF (call: H2020-MSCA-IF-2014, Project ID: 661395). N.J.W. was supported by the Medical Research Council UK (G1000143, MC_UU_12015/1, MC_PC_13048 and MC_U106179471), Cancer Research UK (C864/A14136) and EU FP6 programme (LSHM_CT_2006_037197). E.Z. was supported by the Wellcome Trust (WT098051). J.N.H. was supported by the Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) training program, funded by T32CA160056 (PI: X.-O. Shu) and by VA grant 1I01CX000982. A. Giri was supported by VA grant 1I01CX000982. T.L.E. and D.R.V.E. were supported by grant R21HL121429 from NHLBI, NIH. A.M.H. was supported by VA Award #I01BX003360. C.J.O. was supported by VA Boston Healthcare, Section of Cardiology and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School. The MRC/BHF Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194) and UK National Institute for Health Research Cambridge Biomedical Research Centre. J. Danesh is a British Heart Foundation Professor and NIHR Senior Investigator. L.V.W. holds a GlaxoSmithKline/British Lung Foundation Chair in Respiratory Research. P.E. acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141), and the Medical Research Council (MRC) and Public Health England (PHE) Centre for Environment and Health (MR/L01341X/1). P.E. is a UK Dementia Research Institute (DRI) professor at Imperial College London, funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK. He is also associate director of Health Data Research–UK London, funded by a consortium led by the Medical Research Council. M.J.C. was funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Center at Barts and The London School of Medicine and Dentistry. M.J.C. is a National Institute for Health Research (NIHR) senior investigator, and this work is funded by the MRC eMedLab award to M.J.C. and M.R.B. and by the NIHR Biomedical Research Centre at Barts.

This research has been conducted using the UK Biobank Resource under application numbers 236 and 10035. This research was supported by the British Heart Foundation (grant SP/13/2/30111). Large-scale comprehensive genotyping of UK Biobank for cardiometabolic traits and diseases: UK CardioMetabolic Consortium (UKCMC).

Computing: This work was enabled using the computing resources of (i) the UK Medical Bioinformatics aggregation, integration, visualisation and analysis of large, complex data (UK Med-Bio), which is supported by the Medical Research Council (grant number MR/L01632X/1), and (ii) the MRC eMedLab Medical Bioinformatics Infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). The views expressed in this manuscript 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. C.P.K. is an employee of the US Department of Veterans Affairs. Opinions expressed in this paper are those of the authors and do not necessarily represent the opinion of the Department of Veterans Affairs or the United States Government.

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Central analysis. E.E., H.R.W., D.M.-A., B.M., R.P., H.G., G.N., N.D., C.P.C., I. Karaman, F.L.N., M.E., K.W., E.T., L.V.W.

Writing of the manuscript. E.E., H.R.W., D.M.-A., B.M., R.P., H.G., I.T., M.R.B., L.V.W., P.E., M.J.C. (with group leads E.E., H.R.W., L.V.W., P.E., M.J.C.). All authors critically reviewed and approved the final version of the manuscript.

ICBP-Discovery contributor. (3C-Dijon) S.D., M.S., P. Amouyel, G.C., C.T.; (AGES-Reykjavik) V. Gudnason, L.J.L., A.V.S., T.B.H.; (ARIC) D.E.A., E.B., A. Chakravarti, A.C.M., P.N.; (ASCOT) N.R.P., D.C.S., A.S., S. Thom, P.B.M., P. Sever, M.J.C., H.R.W.; (ASPS) E.H., Y.S., R. Schmidt, H. Schmidt; (B58C) D.P.S., (BHS) A. James, N. Shrine; (BioMe (formerly IPM)) E.P.B., Y. Lu, R.J.F.L.; (BRIGHT) J.C., M.F., M.J.B., P.B.M., M.J.C., H.R.W.; (CHS) J.C.B., K.R., K.D.T., B.M.P.; (Cilento study) M. Ciullo, T. Nutile, D.R., R. Sorice; (COLAUS) M. Bochud, Z.K., P.V.; (CROATIA_Korcula) J. Marten, A.F.W.; (CROATIA_SPLIT) I. Kolcic, O.P., T.Z.; (CROATIA_Vis) J.E.H., I.R., V.V.; (EPIC) K.-T.K., R.J.F.L., N.J.W.; (EPIC-CVD) W.-Y.L., P. Surendran, A.S.B., J. Danesh, J.M.M.H.; (EPIC-Norfolk, Fenland-OMICS, Fenland-GWAS) J.-H.Z.; (EPIC-Norfolk, Fenland-OMICS, Fenland-GWAS, InterAct-GWAS) J.L., C.L., R.A.S., N.J.W.; (ERF) N.A., B.A.O., C.M.v.D.; (Fenland-Exome, EPIC-Norfolk-Exome) S.M.W., FHS, S.-J.H., D.L.; (FINRISK (COROGENE_CTRL)) P.J., K.K., M.P., A.-P.S.; (FINRISK_PREDICT_CVD) A.S.H., A. Palotie, S.R., V.S.; (FUSION) A.U.J., M. Boehnke, F. Collins, J.T., (GAPP) S. Thériault, G.P., D.C., L.R.; (Generation Scotland (GS:SFHS)) T. Boutin, C.H., A. Campbell, S.P.; (GoDARTs) N. Shah, A.S.F.D., A.D.M., C.N.A.P.; (GRAPHIC) P.S.B., C.P.N., N.J.S., M.D.T.; (H2000_CTRL) A. Jula, P.K