Childhood adversity and 5-HTTLPR across mental health outcomes: A transdiagnostic meta-analysis

Childhood maltreatment is associated with increased risk for various psychiatric disorders, although individual responses to early adversity vary. The serotonin transporter-linked polymorphic region (5-HTTLPR) has been examined as a potential moderator of sensitivity to environmental stress, but findings across studies have been inconsistent.

This meta-analysis examined whether 5-HTTLPR polymorphisms moderate the association between childhood adversity and clinically diagnosed psychiatric disorders.

Fourteen studies (N = 3479) were included, representing community, population-based, and clinical samples from multiple regions. Childhood adversity was assessed using validated interviews, questionnaires, or official electronic records.

Systematic searches of eight databases (last updated 3 December 2025) identified studies reporting 5-HTTLPR genotype, childhood adversity, and psychiatric diagnoses. Ratio-of-odds-ratios (ROR) quantifies differences in adversity effects between S-allele carriers and LL homozygotes. Multilevel random-effects models generated pooled estimates. Sensitivity, moderator, and publication-bias analyses were performed. Study quality was assessed using the Newcastle-Ottawa Scale, and certainty of evidence using GRADE.

Pooled analyses indicated no statistically significant interaction between childhood adversity and 5-HTTLPR genotype (ROR = 1.11, 95% CI 0.89-1.37). Analyses restricted to SS-only or SL-only groups and sexual abuse-specific subgroups produced similar results. Heterogeneity was moderate, and small-study effects were borderline. Moderator analyses did not identify consistent influences of diagnosis or ancestry.

Across available studies, evidence for an interaction between childhood adversity and 5-HTTLPR genotype was limited. Unlike previous meta-analyses that focused primarily on symptom-level or trait-based measures, the present study evaluates clinically diagnosed outcomes, offering evidence that 5-HTTLPR is unlikely to represent a robust moderator of adversity effects. These findings may suggest that, within current research parameters, 5-HTTLPR does not show a consistent moderating role in clinically diagnosed psychiatric outcomes.