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87 rare variants associated with blood pressure regulation in meta-analysis of ~1.3 million individuals

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Peer-reviewed

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Article

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Authors

Karthikeyan, Savita 
Prins, Bram P 
Stewart, Isabel D 

Abstract

Genetic studies of blood pressure (BP) to date have mainly analysed common variants (minor allele frequency, MAF>0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF≤0.01) variant-BP associations (P<5x10-8) of which, 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Rare variants, 44% of which were coding, on average had effects ~8 times larger than the mean effects of common variants and indicate potential candidate causal genes at new and known loci e.g. GATA5, PLCB3. BP-associated variants (including rare and common) were enriched in regions of active chromatin in foetal tissues, potentially linking foetal development with BP regulation in later life. Multivariable Mendelian randomisation highlighted 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.

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Journal Title

Nature Genetics

Conference Name

Journal ISSN

1061-4036

Volume Title

52

Publisher

Springer Nature

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All rights reserved
Sponsorship
Medical Research Council (MC_UU_12015/1)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
Praveen Surendran is supported by a Rutherford Fund Fellowship from the Medical Research Council grant MR/S003746/1. Najim Lahrouchi 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). Jacklyn N. Hellwege was supported by the Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) Training Program (T32CA160056, PI X.-O. Shu). Nora Franceschini is supported by the National Institute of Health awards HL140385, MD012765 and DK117445. Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Panos Deloukas’s work was supported by the British Heart Foundation (BHF) grant RG/14/5/30893. Ruth J.F. Loos is funded by R01DK110113, U01HG007417, R01DK101855, R01DK107786. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10  (QTL in Health and Disease) and MRC University Unit Programme Grant MC_PC_U127592696. Mark I. McCarthy* is a Wellcome Senior Investigator (098381; 212259) and an NIHR Senior Investigator (NF-SI-0617-10090). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), and by the Wellcome (090532, 106130, 098381, 203141, 212259). Teresa Ferreira* is supported by the NIHR Biomedical Research Centre, Oxford. Maciej Tomaszewski is supported by British Heart Foundation (PG/17/35/33001 and PG/19/16/34270) and Kidney Research UK (RP_017_20180302).  John Danesh* is funded by the National Institute for Health Research [Senior Investigator Award]. Cecilia M. Lindgren* is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). Joanna M. M. Howson* was funded by the National Institute for Health Research [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 are provided in the supplementary information.