Protein-protein interactions shape trans-regulatory impact of genetic variation on protein expression and complex traits

Most genetic variants influence complex traits by affecting gene regulation. Yet, despite comprehensive catalogs of molecular QTLs, linking trait-associated variants to biological functions remains difficult. In this study, we re-analyzed large maps of protein QTLs (pQTLs) to show that genes with trans-pQTLs but without cis-pQTLs are under strong selective constraints and are highly enriched in GWAS loci. We found that trans-pQTLs and their trans targets are highly enriched in interacting protein pairs, and trans-pQTLs in coding regions are significantly enriched at protein-protein interactions (PPI) interfaces. By leveraging existing PPI annotations for trans-pQTL mapping, we identified 26,028 trans-pQTLs influencing 1,061 PPI clusters. The trans-pQTLs of PPIs colocalized with 66% GWAS loci per trait on average for 50 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 on the same PPIs, pinpointing protein complexes and signaling pathways that show promising therapeutic target potential.