Adverse childhood experiences, genetic predisposition, and lifestyle factors: Roles in cardiometabolic-depressive...

Adverse Childhood Experiences (ACEs) have profound effects on physical and mental health across the lifespan. However, how ACEs influence the co-occurrence and progression patterns between cardiometabolic diseases (CMDs) and depressive disorders remains poorly understood.

This prospective cohort study was conducted on 203,449 UK Biobank participants. Outcomes included incident CMDs (a composite of type 2 diabetes, coronary artery disease, stroke, and heart failure), depressive disorders, their multimorbidity (co-occurrence of both conditions), and mortality. Disease trajectories and transitions were analyzed using multistate models. Both additive and multiplicative interactions of genetic predisposition and healthy lifestyle with ACE exposure were investigated.

During a median follow-up of 14.8 years, 20,152 individuals (9.9 %) developed CMD only, 5859 (2.9 %) developed depressive disorders only, and 1507 (0.7 %) developed multimorbidity. ACE exposure showed dose-response associations with multimorbidity risks (HRs: 1.07-3.89), with stronger associations for transitions starting with depressive disorders (HRs: 1.19-3.89) than transitions starting with CMD (HRs: 1.07-3.61). The probability of progressing from depressive disorders to multimorbidity (12.8-15.5 %) was significantly higher than that from CMD to multimorbidity (4.5-7.2 %) across three ACE groups. Emotional abuse showed the strongest associations with depressive disorders-first transitions. High genetic predisposition amplified ACE-associated risks (up to 8.51-fold for the depressive disorders-CMD transition), while healthy lifestyle attenuated 11-74 % risks.

This study underscores the dose-response effect of ACEs on CMD-depressive disorders multimorbidity, revealing transition-specific vulnerability to early-life adversity. The findings that genetic predisposition amplifies, while healthy lifestyle attenuates ACE-associated risks suggest opportunities for targeted intervention strategies.