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

Abstract

Genetic studies of blood pressure (BP) to date have mainly analysed common variants (minor allele frequency, MAF>0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF≤0.01) variant-BP associations (P<5x10-8) of which, 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Rare variants, 44% of which were coding, on average had effects ~8 times larger than the mean effects of common variants and indicate potential candidate causal genes at new and known loci e.g. GATA5, PLCB3. BP-associated variants (including rare and common) were enriched in regions of active chromatin in foetal tissues, potentially linking foetal development with BP regulation in later life. Multivariable Mendelian randomisation highlighted 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.