Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension

Genome-wide association studies of blood pressure (BP) have identified >1000 loci, but the effector genes and biological pathways at these loci are mostly unknown. Using published association summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation and colocalization to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with 2 BP traits and 84 with all three. For >20% of signals, a single variant accounted for >75% posterior probability, 65 were missense variants in known (SLC39A8, ADRB2, DBH) and previously unreported BP candidate genes (NRIP1, MMP14). In disease-relevant tissues, we colocalized >80 and >400 distinct signals for each BP trait with cis-eQTLs, and regulatory regions from promoter capture Hi-C, respectively. Integrating mouse, human disorder, gene expression and tissue abundance data and literature review, we provide consolidated evidence for 436 BP candidate genes for future functional validation and identify several new drug targets.