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

Abstract

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 meta-analysis summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with #61619;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, tissue expression data and literature review, we provide consolidated evidence for 394 BP candidate genes for future functional validation and identifies several new drug targets.

Beyond Genome-Wide Scans: Advancing Hypertension Genomics Into the Future

“…The transition from identifying genetic variants associated with diseases through GWAS to understanding their functional impacts presents a significant challenge, especially as most GWAS variants are located in the genome’s noncoding regions. Munroe’s team 4 has highlighted a path forward by integrating diverse data sets—including mouse models, human genetic disorders, gene expression profiles, tissue-specific gene abundance, and extensive literature reviews—to nominate 436 blood pressure candidate genes for functional validation. This validation process is essential for bridging the gap between genetic discovery and clinical application.…”