Genetic and environmental determinants of stressful life events and their overlap with depression and neuroticism

Abstract

Background: Stressful life events (SLEs) and neuroticism are risk factors for major depressive disorder (MDD). However, SLEs and neuroticism are heritable and genetic risk for SLEs is correlated with risk for MDD. We sought to investigate the genetic and environmental contributions to SLEs in a family-based sample, and quantify genetic overlap with MDD and neuroticism. Methods: A subset of Generation Scotland: the Scottish Family Health Study (GS), consisting of 9618 individuals with information on MDD, past 6 month SLEs, neuroticism and genome-wide genotype data was used in the present study. We estimated the heritability of SLEs using GCTA software. The environmental contribution to SLEs was assessed by modelling familial, couple and sibling components. Using polygenic risk scores (PRS) and LD score regression (LDSC) we analysed the genetic overlap between MDD, neuroticism and SLEs. Results: Past 6-month life events were positively correlated with lifetime MDD status (β=0.21, r2=1.1%, p=2.5 x 10-25) and neuroticism (β =0.13, r2=1.9%, p=1.04 x 10-37) at the phenotypic level. Common SNPs explained 8% of the phenotypic variance in personal life events (those directly affecting the individual) (S.E.=0.03, p= 9 x 10-4). A significant effect of couple environment was detected accounting for 13% (S.E.=0.03, p=0.016) of the phenotypic variation in SLEs. PRS analyses found that reporting more SLEs was associated with a higher polygenic risk for MDD (β =0.05, r2=0.3%, p=3 x 10-5), but not a higher polygenic risk for neuroticism. LDSC showed a significant genetic correlation between SLEs and both MDD (rG=0.33, S.E.=0.08 ) and neuroticism (rG=0.15, S.E.=0.07). Conclusions: These findings suggest that SLEs should not be regarded solely as environmental risk factors for MDD as they are partially heritable and this heritability is shared with risk for MDD and neuroticism. Further work is needed to determine the causal direction and source of these associations.

Genome-wide by environment interaction studies (GWEIS) of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

“…Chronic stress may influence cognition, decision-making and behaviour eventually leading to higher risk-taking 97 . These conditions may also increase sensitivity to stress amongst vulnerable individuals, including those with depression, who also have a higher propensity to report SLE, particularly dependent SLE 39 . A potential reporting bias in dependent SLE may be mediated as well by heritable behavioural, anxiety or psychological traits such as risk-taking 43,98 .…”

“…Gene-environment correlation denotes a genetic mediation of associations through genetic influences on exposure to, or reporting of, environments 2,38 . Genetic factors predisposing to MDD may contribute to exposure and/or reporting of SLE 39 . To tackle this limitation, measures of SLE can be broken down into SLE likely to be independent of a respondent’s own behaviour and symptoms, or into dependent SLE, in which participants may played an active role exposure to SLE 40,41 .…”

“…To tackle this limitation, measures of SLE can be broken down into SLE likely to be independent of a respondent’s own behaviour and symptoms, or into dependent SLE, in which participants may played an active role exposure to SLE 40,41 . Different genetic influences with a higher heritability for reported dependent SLE than independent SLE 39,42-45 suggest whereas GxE driven by independent SLE is likely to reflect a genetic moderation of associations between SLE and depression, GxE driven by dependent SLE may result from a genetic mediation of the association through genetically driven personality or behavioural traits. To test this we analysed dependent and independent SLE scores separately in Generation Scotland.…”

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

“…To address this limitation and assess this aspect, following Colodro-Conde et al ., we split the 12-items TSLE measure into SLE that are either potentially “dependent” on a participant’s own behaviour (DSLE; therefore, potentially driven by genetic factors) or not (“independent” SLE; ISLE) 46,49 . DSLE are reported to be more heritable and have stronger associations with MDD than ISLE 49,62,63 . In our sample, reporting DSLE is significantly heritable (h 2 SNP = 0.131, s.e.…”

“…Consistent with PRS predicting “personal” SLE in Colodro-Conde et al ., PRS for MDD predicted SLE in our study (see Supplementary Figure 1), although not at the p -threshold at which significant GxE effects were detected. Genetic factors predisposing to MDD may contribute to individuals exposing themselves to, or showing an increased reporting of, SLE via behavioural or personality traits 58,59 . Such genetic mediation of the association between depression and SLE would disclose a gene-environment correlation (i.e.…”