Journal
NATURE GENETICS
Volume 52, Issue 12, Pages 1314-1332Publisher
NATURE RESEARCH
DOI: 10.1038/s41588-020-00713-x
Keywords
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Categories
Funding
- Rutherford Fund Fellowship from the Medical Research Council [MR/S003746/1]
- Foundation De Drie Lichten' in the Netherlands
- Netherlands Cardiovascular Research Initiative
- Dutch Heart Foundation [CVON2012-10 PREDICT, CVON2018-30 PREDICT2]
- BHF Programme Grant [RG/18/13/33946]
- Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) Training Program [T32CA160056]
- National Institute of Health [HL140385, MD012765, DK117445]
- Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grants Scheme - Medical Research Council-Newton Project
- UCL Hospitals NIHR Biomedical Research Centre
- British Heart Foundation (BHF) [RG/14/5/30893, R01DK110113, U01HG007417, R01DK101855, R01DK107786]
- MRC University Unit Programme [MC_UU_00007/10, MC_PC_U127592696, 098381, 212259, NF-SI-0617-10090]
- NIHR Oxford Biomedical Research Centre (BRC)
- Wellcome Trust [098381, 212259, 090532, 106130, 203141]
- NIHR Biomedical Research Centre in Oxford
- H2020 DynaHEALTH action [633595]
- EU [643774]
- British Heart Foundation Research Excellence Award [RE/18/6/34217]
- UKRI Innovation Fellowship at Health Data Research UK
- NIH [R01-DK117445, R01-MD012765, R21-HL140385]
- Medical Research Council Integrative Epidemiology Unit at the University of Bristol
- Medical Research Council [MC_UU_00011/1]
- Fonds de Recherche du Quebec-Sante (FRQS)
- BHF [PG/17/35/33001, PG/19/16/34270]
- Kidney Research UK [RP_017_20180302]
- Evans Medical Foundation
- Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine
- National Institute for Health Research Senior Investigator Award
- Li Ka Shing Foundation
- WT-SSI/John Fell funds
- NIHR Biomedical Research Centre
- National Institutes of Health [5P50HD028138-27]
- NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust)
- British Heart Foundation [PG/19/16/34270, PG/17/35/33001] Funding Source: researchfish
- Kidney Research UK [RP_017_20180302, RP_013_20190305] Funding Source: researchfish
- Medical Research Council [MC_UU_00011/1] Funding Source: researchfish
- MRC [G9521010, MR/L003120/1, MC_UU_00007/10, MC_PC_U127592696, MC_UU_00011/4, MR/S004068/2, MC_UU_12015/1, MC_UU_00026/3, MR/R023484/1, MR/S003746/1, MC_UU_12013/2, G0800270, MR/S004068/1, MC_UU_00011/5, MC_UU_00011/1, MC_UU_00002/7, MC_UU_00006/1, MC_PC_MR/R020183/1] Funding Source: UKRI
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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 similar 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 x 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 similar to 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.
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