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

Seven significant cis-by-trans epistatic effects regulating protein expression were identified in the human plasma proteome, with ABO acting as a central regulator.

• Why it matters: Understanding epistatic effects is crucial for revealing the genetic architecture of gene regulation and complex traits, but progress has been limited by false positives and low discovery power.
• What they did: Using large-scale plasma proteomic data from the UK Biobank Pharma Proteomics Project, the study mapped high-confidence cis-by-trans interactions across all assayed proteins, employing a sandwich variance estimator to control false positives.
• The result: Incorporating these interactions into trait mapping offered little improvement in power, but analysis highlighted ABO's role in modulating protein expression through blood type, suggesting long-term balancing selection within its epistatic network.