The 5‐HTTLPR s/s genotype at the serotonin transporter gene (SLC6A4) increases the risk for depression in a large cohort of primary care attendees: The PREDICT‐gene study

Abstract

Previous reports and meta-analyses have yielded inconclusive results as to whether the s/s genotype at the 5-HTTLPR serotonin transporter polymorphism confers increased risk for depression. We tested the association between s/s genotype and depression in a large cohort (n = 737) of Spanish primary care consecutive attendees participating in a European study on predictors for depression in primary care (PREDICT study). Participants were administered the Composite International Diagnostic Interview (CIDI) depression subscale allowing diagnoses using ICD-10 criteria for depressive episodes. Participants were genotyped to establish 5HTTLPR genotype. Both univariable and multivariable associations between the s/s genotype and depression were tested twice using two different depressive outcomes (ICD-10 depressive episode and ICD-10 severe depressive episode). We found an association between the s/s genotype and both depressive outcomes that was independent of age, sex, family history of psychological problems among first degree relatives and presence of comorbid generalized anxiety disorder. When comparing s/s homozygous versus the rest, the adjusted odds ratio for any ICD-10 depressive episode and for severe ICD-10 depressive episode were 1.50 (95% CI: 1.0-2.2; P = 0.045) and 1.79 (95% CI: 1.1-2.8; P = 0.016), respectively. The association was significantly stronger with increasing severity of depression (chi2 for linear association=6.1; P = 0.013) suggesting a dose-dependent relationship. Our results are consistent with previous reports suggesting a small but independent effect by the s/s 5-HTTLPR genotype increasing the risk for depression.

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

“…Table 2 shows that depression was associated with the 5HTTLPR s/s genotype, as reported in detail elsewhere. 9 In brief, the association between the s/s genotype and depression was independent of age, sex, family history of psychological problems among firstdegree relatives and GAD, but these associations were stronger for more severe depressive episodes. Both outcomes of depression were strongly and independently associated with previous exposure to TLE with initial crude associations remaining robust after adjusting for age, gender, marital status, education and family history of psychological problems (Table 2).…”

“…The PREDICT-Gene study 9 is a case-control association study nested in a cohort of Spanish participants who were part of a larger study on prediction of onset of depression in European primary-care attendees (PREDICT study). A detailed description of the PREDICT study design and its method has been reported elsewhere.…”

“…In addition, no significant differences were found on socio-demographic factors, and the level of depression between the participants included in our genetic analyses with those who refused a genetic specimen or were lost to follow-up at time-3. 9 We did not use the newly reported 5HTTLPR reclassification procedure by additionally genotypying the sample for the so-called A/G variant, 32 which may imply a potential limitation to this study. However, some authors have posed that reclassification of subjects using such new polymorphism seem to render comparable results to the well-established method used by us.…”

“…Its short variant (s allele) reduces the transcriptional efficiency of the gene, resulting in decreased serotonin transporter expression in the neuron. 5 Some association studies have reported an increased risk for depression among s/s genotype carriers, [6][7][8][9][10] although others have reported negative results. [11][12][13] The interplay between genetic and environmental factors in the aetiology of common and complex diseases has been well recognized, 14 but the technology required to explore this relationship has only become available recently.…”

Molecular epidemiology of major depressive disorder

“…Five studies of whites [143][144][145][146][147] found no substantial relationships between the 5-HTTLPR genotype and major depressive disorder. In contrast, seven Caucasian [148][149][150][151][152][153][154] and one non-Ashkenazi Jewish [144] studies found that the SS genotype was associated with a modest increase in risk of depression. Furthermore, one Polish [155] and one German [156] studies found that the SS genotype was associated with a significant increase in risk of depression.…”