Exploring the shared genetic architecture and causal relationship between childhood maltreatment and psychiatric...

Childhood maltreatment (CM) is a major risk factor for psychiatric disorders, yet the shared genetic etiology, potential causal effects, and mediating pathways underlying these associations remain incompletely understood. We investigated the shared genetic architecture, potential causal relationships, and candidate mediating pathways linking genetically proxied reported CM with major psychiatric disorders. Summary statistics were obtained from large-scale genome-wide association studies of CM and 10 psychiatric disorders. Genetic correlations were estimated using linkage disequilibrium score regression and genetic covariance analysis. Shared loci were identified using pleiotropy analysis under the composite null hypothesis. Causal effects and mediation pathways were evaluated using two-sample and two-step Mendelian randomization analyses. CM showed significant positive genetic correlations with 10 psychiatric disorders, with the strongest association observed for post-traumatic stress disorder (rg = 0.71). Mendelian randomization supported potential effects of CM on increased risk for major depressive disorder (OR = 1.61), bipolar disorder (OR = 1.70), schizophrenia (OR = 2.33), attention-deficit/hyperactivity disorder (OR = 2.40), obsessive-compulsive disorder (OR = 1.76), and post-traumatic stress disorder (OR = 1.24). Pleiotropy analysis identified 4113 shared single nucleotide polymorphisms mapped to 167 unique genes. Multi-omics integration prioritized 12 pleiotropic genes enriched in neurodevelopmental, immune, and neuronal signaling pathways. Several candidate mediators were implicated, including lifestyle and behavioral factors (e.g., number of sexual partners, smoking, religious involvement, and leisure screen time), psychosocial traits (loneliness and neuroticism), and physical health indicators. These shared loci and mediation findings should be interpreted as hypothesis-generating candidates for future mechanistic and intervention studies rather than as direct clinical targets.