Mendelian randomisation reveals modifiable pathways and epigenetic markers from childhood maltreatment to neuropsychiatric disorders

Br J Psychiatry. 2025 Nov 4:1-11. doi: 10.1192/bjp.2025.10433. Online ahead of print.

ABSTRACT

BACKGROUND: Observational studies suggested an association between childhood maltreatment and neuropsychiatric disorders; however, mediators remain disputed.

AIMS: We aimed to confirm the relationship between childhood maltreatmen and neuropsychiatric disorders, and to identify addiction-related, biological, behavioural, cognitive, socioeconomic and epigenetic mediators.

METHOD: We used two-sample Mendelian randomisation and publicly available genome-wide association data to evaluate the effect of genetically predicted childhood maltreatment (N = 143 473) on the risk of six neuropsychiatric disorders (up to N = 500 199). We used two-step Mendelian randomisation to determine the proportion of the effect of childhood maltreatment on disorders that was mediated by mediators. We used multivariable Mendelian randomisation to determine the direct effect of childhood maltreatment on disorders accounting for mediators. We used epigenetic Mendelian randomisation to determine the effect of DNA methylation at childhood maltreatment-associated CpG sites on disorders.

RESULTS: Childhood maltreatment was significantly associated with higher risk of attention-deficit/hyperactivity disorder (ADHD) (odds ratio 10.09, 95% CI: 4.76-21.40), major depressive disorder (MDD) (odds ratio 1.89, 95% CI: 1.32-2.70) and schizophrenia (odds ratio: 5.89, 95% CI: 1.46-23.78). We determined that 4.14-22.17% of the effect of childhood maltreatment was mediated by addiction-related behaviours (smoking initiation, leisure screen time and substance abuse), cognitive traits (executive functioning, intelligence and risk tolerance) and educational attainment. We found that the direct effects of childhood maltreatment on ADHD (odds ratio 2.57) and schizophrenia (odds ratio 5.10) were less than the total effects, while the direct effect on MDD (odds ratio 1.95) remained relatively unchanged. We found altered DNA methylation levels at 3, 4 and 19 CpG sites to be significantly associated with ADHD, MDD and schizophrenia, respectively.

CONCLUSIONS: These results emphasise the need for preventative strategies to reduce childhood maltreatment prevalence, including strengthening support for high-risk families and responsive strategies to mitigate consequences for victims, with clinical screening for childhood maltreatment history and holistic approaches addressing addiction-related, cognitive and socioeconomic mediators.

PMID:41186115 | DOI:10.1192/bjp.2025.10433