Abstract
Most genetic variants influence complex traits by affecting gene regulation. Yet, despite comprehensive catalogs of molecular quantitative trait loci (QTLs), linking trait-associated variants to biological functions remains difficult. By re-analyzing large maps of protein QTLs (pQTLs), we found that genes with trans-pQTLs but no cis-pQTLs are under strong selective constraints and are particularly informative in interpreting genome-wide association study (GWAS) loci. We observed that trans-pQTLs and their target proteins are frequently involved in protein-protein interactions (PPIs). Notably, trans-pQTLs are enriched in missense variants and at PPI interfaces, suggesting a key role of PPIs in the trans-regulation of proteome. Using PPI annotations to guide trans-pQTL mapping, we identified 17,662 trans-pQTLs affecting 961 PPI clusters after accounting for blood cell composition effects. These trans-pQTLs colocalized with 36% GWAS loci per trait on average for 27 complex traits, helping in many cases to link GWAS loci to cellular function. Finally, we identified trans-pQTL effects at multiple autoimmune GWAS loci that converge to the same PPIs, pinpointing protein complexes and signaling pathways that show promising therapeutic target potential.