Decoding the Therapeutic Target SVEP1: Harnessing Molecular Trait GWASs to Unravel Mechanisms of Human Disease.

Abstract

Although human genetics has substantial potential to illuminate novel disease pathways and facilitate drug development, identifying causal variants and deciphering their mechanisms remain challenging. We believe these challenges can be addressed, in part, by creatively repurposing the results of molecular trait genome-wide association studies (GWASs). In this review, we introduce techniques related to molecular GWASs and unconventionally apply them to understanding SVEP1, a human coronary artery disease risk locus. Our analyses highlight SVEP1's causal link to cardiometabolic disease and glaucoma, as well as the surprising discovery of SVEP1 as the first known physiologic ligand for PEAR1, a critical receptor governing platelet reactivity. We further employ these techniques to dissect the interactions between SVEP1, PEAR1, and the Ang/Tie pathway, with therapeutic implications for a constellation of diseases. This review underscores the potential of molecular GWASs to guide drug discovery and unravel the complexities of human health and disease by demonstrating an integrative approach that grounds mechanistic research in human biology.