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

LifeLines Cohort Study, EPIC-CVD, EPIC-InterAct, Understanding Society Scientific Group, Million Veteran Program

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1314-1332
Number of pages19
JournalNature Genetics
Volume52
Early online date23 Nov 2020
DOIs
Publication statusPublished - Dec 2020

Fingerprint Dive into the research topics of 'Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals'. Together they form a unique fingerprint.

Cite this