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

Nat Genet. 2020 Dec;52(12):1314-1332. doi: 10.1038/s41588-020-00713-x. Epub 2020 Nov 23.


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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • GATA5 Transcription Factor
  • GATA5 protein, human
  • PLCB3 protein, human
  • Phospholipase C beta

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