Abstract
Background Initially developed to explain the origins of schizophrenia in the 1960s and adapted for the study of depression in the 1980s, the diathesis-stress model states that stress may activate a diathesis or vulnerability, transforming the potential of predisposition into the actuality of psychopathology. Implicit in this theory is that there will be not only additive but multiplicative interactive effects on the liability scale. Polygenic risk scores (PRS) provide a novel opportunity to test the diathesis stress model. We report here a direct test of the diathesis-stress model for depression using the most recent version of PGC-MDD GWAS results (MDD2) and measures of Stressful Life Events (SLEs) and Social Support (SS; lack of SS being considered a stressor). Methods Our sample was comprised of 5,221 individuals from 3,083 families (mean age at questionnaire 35.7, SD=12.2, range 17–85, 65.6% females) with measures of stressful life events and social support and a depression symptom score, as well as DSM‐IV MDD diagnoses for most individuals. PRS were calculated from the imputed genotype dosages, using GWAS summary statistics from the most recent PGC MDD release [July 9th 2016], with the exclusion of the contribution of QIMR, for a final sample of 49,524 cases and 110,074 controls. PRS were used as a direct measure of the vulnerability for depression. In order to estimate the variance in depression explained by the genetic vulnerability, the stressors and their interactions, we fitted linear mixed models controlling for relatedness for the whole sample as well as stratified by sex. The parameters of the model were estimated using GCTA 1.26.0 (student test to test the significance of the fixed effects) that accounts for twin relatedness using a Genetic Relatedness Matrix. Results PRS for MDD significantly predicted the depression score (maximum variance explained =0.46%. p-value= 5.01e-08), which represents a substantial improvement compared to PRS predictions based on the previous PGC-MDD GWAS (PGC1, variance explained = 0.08%, p-value=0.018). The depression score significantly predicted lifetime DSM-IV MDD status (OR=1.96, 95%CI 1.85–2.08, p-value=3.0e-108, N=8,607). The main effects of PSLE, NSLE, and lack of SS were also significant, explaining respectively 12.9%, 0.3% and 3% of the depression score variance, with effects in the expected directions. We show a significant interaction of the PRS with personal life events (0.12% of variance explained, p‐value=0.0076) contributing positively to the risk of depression, predominantly in women. The interaction was not significant in men while explaining almost as much variance as the main effect in women. However, there was no significant difference when comparing the size of the interaction across sexes (p-value=0.21). Discussion Our findings point to an extra risk for individuals with combined vulnerability and high number of reported personal life events beyond what would be expected from the additive contributions of these factors to the liability for depression, supporting the multiplicative diathesis‐stress model for this disease. Additionally, our results suggest possible differences in the aetiology of depression between women and men.
Highlights
A popular explanation for the aetiology of depression is the diathesis–stress model.[1,2,3,4,5,6] Initially developed to explain the origins of schizophrenia in the 1960s5,6 and adapted for the study of depression in the 1980s,1–4 this model states that stress may activate a diathesis or vulnerability, transforming the potential of predisposition into the actuality of psychopathology.[7]
Lack of social support (SS) predicted more of the depression score in women than it did in men but there were no other differences between sexes that reached significance
The variance explained by Polygenic risk scores (PRS) main effect plus the interaction was comparable in men (0.73%) and women (0.60%)
Summary
A popular explanation for the aetiology of depression is the diathesis–stress model.[1,2,3,4,5,6] Initially developed to explain the origins of schizophrenia in the 1960s5,6 and adapted for the study of depression in the 1980s,1–4 this model states that stress may activate a diathesis or vulnerability, transforming the potential of predisposition into the actuality of psychopathology.[7] The model proposes that there is a synergism between the diathesis and stress that yields an effect beyond their combined separate effects into depressive symptomatology and the effects of stress on the depression risk are dependent on the diathesis Implicit in this theory is that there will be additive but multiplicative interactive effects on the liability scale.[7]. The diathesis–stress theory and research have been criticised for being ‘unproductive, either theoretically or empirically’.8
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