Plasma proteomic signatures of childhood adversity

What are the plasma proteomic signatures of childhood adversity, and how do they contribute to the associations of childhood adversity with diseases? Here, we first comprehensively mapped 1,045 diseases (396 prevalent and 649 incident) to childhood adversity, revealing robust associations with 199 prevalent and 337 incident diseases, notably psychiatric diorders, alongside musculoskeletal, gastrointestinal, respiratory and genitourinary diseases (N = 150,147). We then characterized the plasma proteomic signatures of childhood adversity using 2,919 plasma proteins and identified 381 proteins significantly associated with childhood adversity, predominantly enriched in biological pathways pertaining to immune function and metabolism (N = 12,933). Two sample Mendelian randomization analysis further revealed that childhood adversity causally contributed to the abundance of certain proteins (i.e., PIGR and IL17D) implicated in mucosal immunity and chronic inflammation, which partially mediated the links between childhood adversity and 51 incident diseases, including gastrointestinal, psychiatric and musculoskeletal diseases. Finally, we developed a novel proteomic childhood adversity score (PCAS) for assessing childhood adversity, which significantly improved the prediction for several incident diseases. The findings underscore the potential of plasma proteins in elucidating the biological embedding of childhood adversity, and highlight their promising therapeutic value for reducing disease burdens among adults who experienced childhood adversity.