Polygenic risk scores (PRSs) capture the genetic architecture of common diseases by aggregating genome-wide genetic variation into a single score that reflects an individual’s disease risk. These present new opportunities to identify molecular pathways involved in disease pathogenesis. We performed association analysis between PRSs and 3,442 plasma proteins in 3,175 healthy individuals, identifying 48 proteins whose levels associated with PRSs for coronary artery disease, chronic kidney disease, or type 2 diabetes. Integrative analyses of human and mouse data to characterise these associations revealed a role for polygenic effects on several well-known causal disease proteins and identified promising novel targets for future follow-up. We found implicated PRS-associated genes were responsive to dietary intervention in mice and showed strong evidence of druggability in humans, consistent with PRS-associated proteins having therapeutic potential. Overall, our study provides a framework for polygenic association studies, demonstrating the power of PRSs to unravel novel disease biology.

Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases