Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

Abstract

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations.

5-HTTLPR × stress hypothesis: is the debate over?

“…Although our data require replication, they add to the findings by Culverhouse et al 1 and the broader debate. They may help account for the lack of strong evidence supporting the interaction hypothesis.…”

“…They may help account for the lack of strong evidence supporting the interaction hypothesis. 1 Although none of our findings are compatible with a linear/additive allelic model, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and psychological load (stressful events and past major depression) suggest opposite recessive models, and resilience reflects heterosis. Indeed, a heterosis effect has been found in up to 50% of all gene association studies 4 and has already been reported with 5-HTTLPR in a variety of psychiatric phenotypic expressions.…”

“…We read with great interest the impressive meta-analysis by Culverhouse et al, 1 the largest and most comprehensive study to investigate whether 5-HTTLPR genotype modifies the association between stress and depression. Their findings based on 31 studies totaling 38 802 individuals of European ancestry do not support the interaction hypothesis between 5-HTTLPR genotype and stress (childhood maltreatment and broad life stress) on depression (lifetime or current).…”

“…Culverhouse et al 1 should be commended for their attempts to rule out other factors, which may explain the divergence in prior study findings, including those of previous meta-analyses. However, there are other explanations that were not explored and could also have a role, such as interactions with other genes or variants, causing a hidden stratification of the sample such that the depression phenotype would be associated with either one set of homozygotes or the alternate homozygote set.…”

“…Age may also be an important factor to consider and was adjusted for in the models by Culverhouse et al 1 However, most studies involved adolescents or young adults with only two studies specifically including older adults: the Esprit study and the Heart and Soul Study of outpatients with coronary heart disease. 1 As a consequence, they could only perform sub-group analysis in a specific age group (early adulthood, 21-30 years).…”