Childhood adversity has been linked to many types of diseases; however, the underlying biological mechanisms remain inadequately explored, hindering the development of preventive programs and targeted interventions. The plasma proteome has become a promising tool for investigating the mechanisms underlying disease development in recent years. 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 in 150,147 participants (median follow-up: 13.8 years). We then characterized the plasma proteomic signatures of childhood adversity using 2,919 plasma proteins in a subsample of 12,933 participants, and further explored the mediating roles of these proteins in linking childhood adversity to diseases. The results revealed robust associations of childhood adversity with 198 prevalent and 338 incident diseases, notably psychiatric disorders, alongside musculoskeletal, gastrointestinal, respiratory and genitourinary diseases. A total of 381 plasma proteins were identified associated with childhood adversity, predominantly enriched in biological pathways pertaining to immune function and metabolism. A 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. Moreover, two MR-identified proteins partially mediated the links between childhood adversity and 51 incident diseases, including gastrointestinal, psychiatric and musculoskeletal diseases. Finally, we developed a novel proteome-based measure of childhood adversity, termed proteomic childhood adversity score, which significantly improved the predictive performance of models for multiple incident diseases compared with the self-reported childhood adversity score. The findings underscore the potential of plasma proteins in elucidating the biological mechanisms linking childhood adversity to various diseases, and highlight their promising therapeutic value for reducing disease burdens among adults who experienced childhood adversity.