The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort

Abstract

We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X 2 = 4.7, P = 0.09 (crude), LR-X 2 = 6.4, P = 0.04 (adjusted); ICD-10 severe depressive episode: LR X 2 = 6.9, P = 0.032 (crude), LR-X 2 = 8.1, P = 0.017 (adjusted)).

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…48 Six studies were cross-sectional surveys. 30,31,34,37,39,41,45 One study used a combined cohort/case-control design, selecting participants with extreme scores on either environmental adversity or depression for genotyping. 40 One study examined individuals exposed to a major stressor (myocardial infarction).…”

“…The weak or non-significant associations between SLEs and depression in these studies suggest problems with the validity of self-report measures of SLE 50 and, in the study by Gillepie and colleagues 44 possible inaccuracies of the retrospective assessment of depression. 51 Serotonin transporter gene-environment interactionunselected primary care attendees, 37 three studies used convenience samples of students or teachers; 34,35,43 three studies used enriched samples selected based on experience of childhood abuse, 31 high levels of social adversity and depression 40 or extremes on neuroticism 45 and two studies used clinical samples of depressed patients. 33,36 Sample size is a major determinant of power to detect G Â E. 52 It is therefore notable that the two studies with largest samples produced negative findings.…”

“…Taken at face value, there were eleven replications, 15,[29][30][31][32][33][34][35][36][37][38][39] three partial replications in females only, [40][41][42] and three non-replications. [43][44][45] Importantly, two studies with very large samples were negative.…”

“…126,136 However, the only way to obviate the retrospective recall bias is to obtain an objective record of the SLE. 137 Of the reviewed studies, five used structured interviews, 11,15,33,35,36 one used semistructured interview, 42 nine used questionnaires 29,32,34,37,40,41,[43][44][45] and one used objective record of child abuse. 31 All studies that used a structured interview to assess SLEs have found a G Â E with the 5-HTTLPR s allele.…”

“…151 The breath and depth of the phenotype Comorbidity, depression, substance abuse and suicide Most known environmental and genetic risk factors are not diagnosis-specific. The studies summarised above reported that 5-HTTLPR genotype moderates the effect of environmental adversity on the onset of diagnosed depression, 11,15,32,35,37 on a continuous measure of depressive symptoms, 29,31,34,[40][41][42] on severity of depression within a group of diagnosed patients 36 and on suicidality. 11,47 Additional recent studies have found similar relationship for alcohol and drug use 43,59,152 and for violent criminal behaviour.…”