Repository logo
 

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

Accepted version
Peer-reviewed

Change log

Authors

Surendran, Praveen 
Lahrouchi, Najim 
Ntalla, Ioanna 
Karthikeyan, Savita 

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.

Description

Keywords

Blood Pressure, GATA5 Transcription Factor, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Hypertension, Mutation, Phospholipase C beta, Polymorphism, Single Nucleotide

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

52

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
Medical Research Council (G0800270)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Medical Research Council (MR/S003746/1)
British Heart Foundation (RG/18/13/33946)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MR/S004068/1)
MRC (MC_UU_00006/1)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
European Research Council (268834)
Medical Research Council (MR/N003284/1)
Medical Research Council (MC_U106179471)
Medical Research Council (MC_UU_00002/7)
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (G1000143)
Medical Research Council (G0401527)
Medical Research Council (G0800270/1)
Medical Research Council (G0401527/1)
P. Surendran is supported by a Rutherford Fund Fellowship from the Medical Research Council grant MR/S003746/1. N. 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). J. N. Hellwege was supported by the Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) Training Program (T32CA160056, PI X.-O. Shu). N. Franceschini is supported by the National Institute of Health awards HL140385, MD012765 and DK117445. F. W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. P. Deloukas’s work was supported by the British Heart Foundation (BHF) grant RG/14/5/30893. R. J. F. Loos is funded by R01DK110113, U01HG007417, R01DK101855, R01DK107786. C. 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. M. 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). T. Ferreira* is supported by the NIHR Biomedical Research Centre, Oxford. M. Tomaszewski is supported by British Heart Foundation (PG/17/35/33001 and PG/19/16/34270) and Kidney Research UK (RP_017_20180302). J. Danesh* is funded by the National Institute for Health Research (Senior Investigator Award). C. 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). J. M. M. Howson* was funded by the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust).