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

TitleDiscovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.
Publication TypeJournal Article
Year of Publication2020
AuthorsSurendran P, Feofanova EV, Lahrouchi N, et al.
Corporate AuthorsLifeLines Cohort Study, EPIC-CVD, EPIC-InterAct, Understanding Society Scientific Group, Million Veteran Program
JournalNat Genet
Volume52
Issue12
Pagination1314-1332
Date Published2020 12
ISSN1546-1718
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), 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.

DOI10.1038/s41588-020-00713-x
Alternate JournalNat Genet
PubMed ID33230300
Grant ListRG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
SP/09/002 / BHF_ / British Heart Foundation / United Kingdom
G0800270 / MRC_ / Medical Research Council / United Kingdom
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
MR/S003746/1 / MRC_ / Medical Research Council / United Kingdom
RG/18/13/33946 / BHF_ / British Heart Foundation / United Kingdom
T32 CA160056 / CA / NCI NIH HHS / United States
098381 / WT_ / Wellcome Trust / United Kingdom
NF-SI-0617-10090 / DH_ / Department of Health / United Kingdom
RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom
R01 DK110113 / DK / NIDDK NIH HHS / United States
U01 HG007417 / HG / NHGRI NIH HHS / United States
R01 DK101855 / DK / NIDDK NIH HHS / United States
R01 DK107786 / DK / NIDDK NIH HHS / United States
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
MC_PC_U127592696 / MRC_ / Medical Research Council / United Kingdom
212259 / WT_ / Wellcome Trust / United Kingdom
090532 / WT_ / Wellcome Trust / United Kingdom
106130 / WT_ / Wellcome Trust / United Kingdom
203141 / WT_ / Wellcome Trust / United Kingdom
RE/18/6/34217 / BHF_ / British Heart Foundation / United Kingdom
R01 DK117445 / DK / NIDDK NIH HHS / United States
R01 MD012765 / MD / NIMHD NIH HHS / United States
R21 HL140385 / HL / NHLBI NIH HHS / United States
MC_UU_00011/1 / MRC_ / Medical Research Council / United Kingdom
MC_UU_00011/4 / MRC_ / Medical Research Council / United Kingdom
MC_UU_00011/5 / MRC_ / Medical Research Council / United Kingdom
PG/17/35/33001 / BHF_ / British Heart Foundation / United Kingdom
PG/19/16/34270 / BHF_ / British Heart Foundation / United Kingdom
P50 HD028138 / HD / NICHD NIH HHS / United States