Exploring the genetic causality of childhood maltreatment on multiple risk-related outcomes using Mendelian randomization: evidence from European-Ancestry GWAS

<b>Background:</b> Childhood maltreatment (CM) has been implicated as a risk factor for various maladaptive behaviours in adulthood, but evidence from genetic epidemiology remains limited. This study aimed to assess the potential causal effects of genetically proxied liability to CM on multiple risk-related behaviours using Mendelian randomization (MR) in European-ancestry populations.<b>Methods:</b> MR analysis was conducted using publicly available GWAS summary statistics to assess the effects of CM on seven outcomes: aggressive behaviour (AB), automobile speeding propensity (ASP), alcohol drinking (AD), smoking behaviour (SB), general risk tolerance (GRT), age at first sexual intercourse (AFI), and lifetime number of sexual partners (LSP). The primary analysis used the inverse-variance weighted (IVW) method, with additional checks via MR-Egger and weighted median methods. CM was instrumented with SNPs identified in GWAS of self-reported maltreatment; hence the exposure reflects a genetically proxied liability to report CM and may capture gene-environment correlation rather than a direct biological determinant.<b>Results:</b> Genetically proxied CM liability was significantly associated with increased risk of AB (OR = 1.19, 95% CI: 1.09-1.30, PFDR < 0.001), SB (OR = 1.16, 95% CI: 1.05-1.28, PFDR = 0.006), GRT (<i>β</i> = 0.21, 95% CI: 0.12-0.29, PFDR < 0.001), and earlier AFI (<i>β</i> = -0.36, 95% CI: -0.49 to -0.23, PFDR < 0.001). A nominal association was found with ASP (<i>β</i> = 0.07, 95% CI: -0.03-0.17, PFDR < 0.001). CM showed a weak protective effect against AD (OR = 0.96, 95% CI: 0.94-0.99, PFDR = 0.013). No significant effect was observed on LSP (<i>β</i> = 0.20, 95% CI: 0.13-0.28, PFDR = 0.192).<b>Conclusion:</b> This study provides genetically informed evidence suggesting that a higher liability to CM exposure may increase the likelihood of aggression, smoking, risk-taking, and early sexual initiation. These findings underscore the long-term behavioural consequences of early adversity and highlight the importance of preventive interventions.