Serotonin transporter gene moderates childhood maltreatment's effects on persistent but not single-episode depression: replications and implications for resolving inconsistent results

Abstract

Background: Genetic and environmental factors shape life-long vulnerability to depression, but most gene-environment interaction (G×E) research has focused on cross-sectional assessments rather than life-course phenotypes. This study tests the hypothesis that the G×E involving the length polymorphism in the serotonin-transporter-gene-linked-promoter-region (5-HTTLPR) and childhood maltreatment is specific to depression that runs a persistent course in adulthood.

Methods: The hypothesis is tested in two cohorts. Men and women in the Dunedin Study (N=847), New Zealand, followed to age 32 years with 96% retention and women in the E-Risk Study (N=930), England, followed to age 40 years with 96% retention. Diagnoses of past-year major depressive episode were established at four separate assessments. Depression diagnosed on two or more occasions was considered persistent.

Results: In both cohorts, statistical tests of gene-environment interactions showed positive results for persistent depression but not single-episode depression. Individuals with two short 5-HTTLPR alleles and childhood maltreatment had elevated risk of persistent but not single-episode depression.

Limitations: Some cases of recurrent depression may have been misclassified as single-episode due to non-contiguous assessment windows, but this would have a conservative effect on the findings. Chronic and recurrent depression could not be reliably distinguished due to non-contiguous periods of assessment. Therefore, the term persistent depression is used to describe either chronic or recurrent course.

Conclusions: The specific effect on persistent depression increases the significance of this G×E for public health. Research that does not distinguish persistent course may underestimate G×E effects and account for some replication failures in G×E research.

Fig. 1

Proportion of individuals with persistent depression (panels A, B) and single-episode depression (panels C, D) by childhood maltreatment and serotonin transporter genotype in the Dunedin (panels A, C) and E-Risk (panels B, D) cohorts. The y axis shows the probability of being diagnosed with past year major depression at two or more of the four assessments by level of childhood maltreatment and 5-HTTLPR genotype (LL, SL, and SS). In the Dunedin cohort, maltreatment is a composite trichotomous measure based on observer ratings, parent reports and self-reports (0 = None, 1 = Probable, 2 = Definite). In the E-risk study, maltreatment is a rounded average score on the Childhood Trauma Questionnaire (0 = None, 1 = Mild, 2 = Moderate, 3 = Severe). The number of individuals included in each subgroup is given above each bar.

Fig. 2

Proportion of individuals with past-year diagnosis of major depression at each assessment in the Dunedin and E-Risk cohorts by level of childhood maltreatment and serotonin transporter genotype. Dunedin: Time 1 = age 18, Time 2 = age 21; Time 3 = age 26, Time 4 = age 32; E-Risk: Time 1 = mean age 33, Time 2 = mean age 35; Time 3 = mean age 38, Time 4 = mean age 40; 5-HTTLPR genotype is marked by “LL”, “LS” and “SS” above each group of bars. In the Dunedin cohort, maltreatment is a composite trichotomous measure based on observer ratings, parent reports and self-reports (0 = None, 1 = Probable, 2 = Definite). In the E-risk study, maltreatment is a rounded average score on the Childhood Trauma Questionnaire (0 = None, 1 = Mild, 2 = Moderate, 3 = Severe). For the number of individuals included in each subgroup, please see Fig. 1.