87 RARE VARIANTS ASSOCIATED WITH BLOOD PRESSURE IN META-ANALYSIS OF ∼1.32 MILLION INDIVIDUALS

Abstract

Objective: Elevated blood pressure (BP) is a major risk-factor for cardiovascular disease worldwide with complications accounting for ∼10.7 million premature deaths annually. Most prior genetic studies of BP explored Single Nucleotide Variants (SNVs) with minor allele frequency [MAF] > 0.01, with the majority of identified SNVs being non-coding, the causal gene for a majority of the known BP loci remaining unknown. We aimed to explore the role of rare variants on BP, elucidate candidate causal BP genes, to further our understanding of BP regulation. Design and method: The Exome array facilitates analyses of rare (MAF < = 0.01) coding variants with potential functional consequences. Over 80% of SNVs on the array are rare, ∼6% are low-frequency (0.05 > = MAF > 0.01) and ∼80% are missense, implicating a candidate causal gene through changes to the amino acid sequence. We performed an Exome Array-Wide Association Study (EAWAS) of ∼247,000 SNVs in ∼1.32 million participants from 95 studies to identify SNVs associated with SBP, DBP, PP and hypertension. We additionally performed a rare variant Genome-Wide Association Study (RV-GWAS) of ∼29 million imputed and genotyped SNVs in ∼670,000 participants (UKBiobank, MVP). Results: We discovered 105 new BP-associated genomic regions, containing 9 rare SNV-BP associations in the EAWAS and 23– in the RV-GWAS (P < 5 × 10–8). A further 55 rare variants were independent novel SNVs within known BP-associated loci in the RV-GWAS. Eighty seven BP-associated rare variants highlight potential candidate causal genes (e.g. GATA-binding protein-5, Phospholipase-C Beta-3), with 17% located in or near potentially druggable genes (encoding proteins predicted to be modulated by a drug-like molecule, e.g. Nuclear Receptor subfamily-3 group-C member-2, Natriuretic Peptide-A). Both rare and common BP-associated variants were enriched in regions of active chromatin in foetal tissues, linking foetal development with BP regulation in later life. Multivariable Mendelian randomisation highlight inverse effects of elevated SBP and DBP on large artery stroke. Conclusions: Our study is the largest analysis of rare variants to date, revealing candidate genes at new and previously reported BP loci, highlighting potential therapeutic targets. We also report new observations from both rare and common loci enriching our understanding of genetic BP regulation in health and disease.