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

Area of Science:

• Behavioral Genetics
• Psychiatric Genetics
• Epidemiology

Background:

• Observational studies link child maltreatment to externalizing disorders like ADHD, conduct disorder, ASPD, and SUD.
• Gene-environment correlations can confound observational research, necessitating causal inference methods.

Purpose of the Study:

• To establish causal inference between child maltreatment and externalizing phenotypes using Mendelian Randomization (MR).
• To investigate the genetic overlap and a potential common externalizing factor (EXT).

Main Methods:

• Utilized genome-wide association study (GWAS) summary data for child maltreatment and various externalizing disorders (ADHD, CD, ASPD, AUD, OUD, CUD).
• Employed Mendelian Randomization (MR) and pleiotropy-robust methods.
• Generated a 'common externalizing factor' (EXT) using genomic structural equation modeling.

Main Results:

• Genetically predicted childhood maltreatment was significantly associated with ADHD, AUD, and the common externalizing factor (EXT).
• Results were consistent across different MR analyses and pleiotropy-robust methods.
• Two genes (CADM2, SEMA6D) showed strong associations in both EXT and Externalizing Consortium (EXT-CON) GWAS.

Conclusions:

• Confirms a common externalizing factor and increased vulnerability due to child maltreatment, with implications for prevention.
• Suggests specific influences impact individual phenotypes separately, despite a common underlying factor.