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 associated 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 associated with lifetime MDD status (β=0.21, r 2=1.1%, p=2.5 x 10 -25) and neuroticism (β =0.13, r 2=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, r 2=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 (r G=0.33, S.E.=0.08 ) and neuroticism (r G=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.

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” of a participant’s own behavior (DSLE; therefore, potentially driven by genetic factors) or not (“independent” SLE; ISLE) 45,48 . DSLE are reported to be more heritable and have stronger associations with MDD than ISLE 48,6157 . In our sample, DSLE is significantly heritable ( h 2 SNP = 0.131, s.e.…”

“…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 behavioral or personality traits 57,58 . Such genetic mediation of the association between depression and SLE would disclose a gene-environment correlation (i.e., genetic effects on the probability of undergoing a SLE) that hinders interpretion of our findings as pure GxE effects 59,60 .…”

Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease

“…Smaller studies on genetic determinants of stressful life events showed a significant and robust genetic association between stressful life events and depression. 58 Despite these correlations, the genetic studies of response to stress-related events are not uniform, with various different triggers being investigated. Each individual trigger study is much smaller than the large, relatively uniform studies of depression, thus supporting our use of depression as the best proxy for stress to run the most powered genetic correlation analyses possible.…”

The moderating role of resilience resources in the association between stressful life events and symptoms of postpartum depression

“…Other resilience resources that may moderate the association between stressful life events and postpartum depression are self-esteem, purpose in life, and perceived social support, which have all been related to resilience in other populations experiencing high levels of stress (Bartrés-Faz et al, 2018;Kidd and Shahar, 2008;Julian et al, 2020). Additionally, research suggests that there may be common underlying personality factors that could contribute to both levels of resilience resources and experiencing stressful events (Clarke et al, 2019). Future studies might examine other common personal factors contributing to both higher stressful life events and optimism or mastery, such as neuroticism.…”