Robust cis-by-trans epistasis in the human plasma proteome highlights an ABO-centered interaction network

Detecting and interpreting epistatic effects in the human genome is essential for a complete understanding of the genetic architecture of gene regulation and complex traits. Progress in this area, however, has been hindered by limited discovery power and an abundance of false positives. Here, leveraging large-scale plasma proteomic data from the UK Biobank (UKB) Pharma Proteomics Project (PPP), we systematically map high-confidence cis-by-trans epistatic effects regulating protein expression. To reduce the multiple-testing burden, we focus on protein-level rather than variant-level interaction effects, and we employ a sandwich variance estimator to control false positives, as validated by extensive simulations. We applied the approach to identify cis-by-trans interactions across all proteins assayed in UKB-PPP and detected seven significant epistatic effects. Incorporating these interactions into protein-wide association studies is highly prone to false positives. We thus developed a principled framework but found that they offered little improvement in trait mapping power, likely because their effects on protein-expression variance are outweighed by additive effects. Analysis of the biological and evolutionary context of our detected epistatic interactions pointed to ABO as a central regulator that appears to modulate mean protein expression for several trans-chromosomal targets through its effects on blood type, potentially driving long-term balancing selection on loci within its epistatic network. Together, our results clarify both the biological relevance and the practical limitations of epistasis-aware analysis in human proteomic regulation.