A validation of the diathesis-stress model for depression in Generation Scotland

Abstract

Depression has well-established influences from genetic and environmental risk factors. This has led to the diathesis-stress theory, which assumes a multiplicative gene-by-environment interaction (GxE) effect on risk. Recently, Colodro-Conde et al. empirically tested this theory, using the polygenic risk score for major depressive disorder (PRS, genes) and stressful life events (SLE, environment) effects on depressive symptoms, identifying significant GxE effects with an additive contribution to liability. We have tested the diathesis-stress theory on an independent sample of 4919 individuals. We identified nominally significant positive GxE effects in the full cohort (R2 = 0.08%, p = 0.049) and in women (R2 = 0.19%, p = 0.017), but not in men (R2 = 0.15%, p = 0.07). GxE effects were nominally significant, but only in women, when SLE were split into those in which the respondent plays an active or passive role (R2 = 0.15%, p = 0.038; R2 = 0.16%, p = 0.033, respectively). High PRS increased the risk of depression in participants reporting high numbers of SLE (p = 2.86 × 10−4). However, in those participants who reported no recent SLE, a higher PRS appeared to increase the risk of depressive symptoms in men (β = 0.082, p = 0.016) but had a protective effect in women (β = −0.061, p = 0.037). This difference was nominally significant (p = 0.017). Our study reinforces the evidence of additional risk in the aetiology of depression due to GxE effects. However, larger sample sizes are required to robustly validate these findings.

Childhood Adoption and Mental Health in Adulthood: The Role of Gene-Environment Correlations and Interactions in the UK Biobank

“…Our findings are in line with two recent studies, which found no evidence for an interaction between a PRS for major depression and self-reported childhood trauma in adulthood (21) and in childhood/youth (24), respectively. Two studies (37,38), applying similar methods but using self-reported recent SLEs (in adulthood), reported a significant interaction effect in line with the diathesis-stress model. However, the interaction could be induced by the self-reported stress likely being correlated with both genetic risk for depression and the depression outcome, resulting in those who are at higher risk for depression and possibly experiencing depressive symptoms reporting (and subjectively experiencing) more life stress (i.e., recall bias) (37).…”

The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders

“…Explanatory power is smaller again for hypothesised multiplicative interactions between PRS and adverse life events (e.g. 0.12%; Arnau-Soler et al, 2019; Colodro-Conde et al, 2018). There is no evidence that any extant G × E score is clinically useful as a risk tool: early studies are showing some promise with the polygenetic risk approach (Fang et al, 2020), but effect sizes lack clinical utility.…”

Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum

“…Similarly, several environmental exposures have been associated with a schizophrenia spectrum disorder, such as childhood adversities, cannabis use, urbanicity, migration, ethnic minorities, hearing impairment, and perinatal factors (Linszen et al ., 2016; Radua et al ., 2018; Stilo and Murray, 2019). In accordance with the diathesis-stress model, there is evidence supporting gene–environment interaction in the aetiology of schizophrenia (Guloksuz et al ., 2019) and mood disorders (Geoffroy et al ., 2013; Colodro-Conde et al ., 2018; Arnau-Soler et al ., 2019 a , 2019 b ). A recent case-control study found evidence for additive interactions between molecular genetic liability for schizophrenia (i.e.…”