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

Seven significant cis-by-trans epistatic effects regulate human plasma protein expression, with ABO acting as a central modulator in a complex interaction network.

• Why it matters: Understanding epistatic effects is crucial for revealing the genetic architecture of gene regulation and complex traits, but limited discovery power and false positives have hindered progress.
• What they did: Using large-scale plasma proteomic data from the UK Biobank and a robust statistical framework, researchers mapped high-confidence cis-by-trans interactions across all assayed proteins, identifying seven significant effects.
• The result: While these interactions highlight biological relevance, they offered limited improvement in trait mapping power, emphasizing the dominant role of additive effects and the central influence of ABO in modulating protein expression.