Child maltreatment as transdiagnostic risk factor for the externalizing dimension: a mendelian randomization study

Observational studies indicate that child maltreatment raises the risk of externalizing spectrum disorders, such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), antisocial personality disorder (ASPD), and substance use disorder (SUD), which often co-occur, suggesting a shared externalizing dimension. However, there is a lack of comprehensive investigations utilizing methods such as Mendelian Randomization (MR) to examine causation while also accounting for pleiotropic effects potentially caused by gene-environment correlations (rGE). Furthermore, the dimensional perspective has not yet been considered. To evaluate causality between child maltreatment and the externalizing phenotypes, we used genome-wide association study (GWAS) summary data for child maltreatment (143,473 participants), ADHD (20,183 cases; 35,191 controls), CD (451 cases, 256,859 controls), ASPD (381 cases, 252,877 controls), alcohol use disorder (AUD; 13,422 cases, 244,533 controls), opioid use disorder (OUD; 775 cases, 255,921 controls), and cannabinoid use disorder (CUD; 14,080 cases, 343,726 controls). We also generated a latent variable termed ‘common externalizing factor’ using genomic structural equation modeling. Genetically predicted childhood maltreatment was consistently associated with ADHD (odds ratio [OR], 10.09; 95%-CI, 4.76-21.40; P=1.63 × 10-09), AUD (OR, 3.72; 95%-CI, 1.85-7.52; P=2.42 × 10-04), and the externalizing factor (OR, 2.64; 95%-CI, 1.52-4.60; P=5.80 × 10-04). Results were apparent across different analyses and pleiotropy-robust methods, including approaches accounting for rGE. A second childhood maltreatment GWAS confirmed results for the externalizing factor. These findings confirm the existence of a common externalizing factor and increased vulnerability caused by child maltreatment, carrying implications for prevention. However, the diverging results across externalizing disorders suggest the presence of additional specific influences affecting individual phenotypes.