Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene

Abstract

In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.

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

“…Prospective cohort study design has been used in seven studies; 11,15,29,[42][43][44] although these studies were prospective in nature and included repeated assessments, the depression and SLE were typically assessed at the same time point, leaving the possibility that recall of SLEs may be influenced by the depressed state. 48 Six studies were cross-sectional surveys.…”

“…40,42 The G Â E interaction is consistently positive in young adults. 11,15,29,33,35 Note that in the study of Mandelli and colleagues 33 the middle-aged participants are retrospectively interviewed about events preceding their first affective episode, which occurred on average in their early 30s. Even in a study where positive results were reported separately for both genders, the G Â E was stronger in females.…”

“…[4][5][6][7] In the last five years, G Â E involving specific gene polymorphisms has been identified in animals 8,9 and humans. [10][11][12][13] Encouragingly, replications 14,15 and a positive metaanalysis 16 indicate that measuring environment improves the reliability of genetic research.…”

“…In 2003, Caspi et al 11 reported that carriers of the short ('s'), transcriptionally less active, allele of common functional polymorphism (5-HTTLPR) in the promoter of the serotonin transporter gene (5-HTT) are more likely to develop depression following stressful life events or childhood abuse than individuals homozygous for the long ('l') allele. This demonstration of G Â E has attracted a large number of replication attempts that have used varied methodologies in diverse samples.…”

Associations between neurocognitive functioning and social and occupational resilience among South African women exposed to childhood trauma

“…This is important, because different types of traumatic exposure have differential effects on outcome (Brewin, Andrews, & Valentine, 2000). Trauma occurring in early life may have particularly strong effects on neurocognitive function given the multiple developmental changes in the brain that are occurring and the subsequent effects on extinction learning (Caspi et al, 2003; Gould et al, 2012; Pattwell et al, 2012; Slopen, Koenen, & Kubzansky, 2014). Animal studies have shown that early life stress permanently affects extinction learning and fear-related memory (Chocyk et al, 2014).…”