Abstract
Polygenic risk scores (PRS) for depression correlate with depression status and chronicity, and provide causal anchors to identify depressive mechanisms. Neuroticism is phenotypically and genetically positively associated with depression, whereas psychological resilience demonstrates negative phenotypic associations. Whether increased neuroticism and reduced resilience are downstream mediators of genetic risk for depression, and whether they contribute independently to risk remains unknown. Moderating and mediating relationships between depression PRS, neuroticism, resilience and both clinical and self-reported depression were examined in a large, population-based cohort, Generation Scotland: Scottish Family Health Study (N = 4166), using linear regression and structural equation modelling. Neuroticism and resilience were measured by the Eysenck Personality Scale Short Form Revised and the Brief Resilience Scale, respectively. PRS for depression was associated with increased likelihood of self-reported and clinical depression. No interaction was found between PRS and neuroticism, or between PRS and resilience. Neuroticism was associated with increased likelihood of self-reported and clinical depression, whereas resilience was associated with reduced risk. Structural equation modelling suggested the association between PRS and self-reported and clinical depression was mediated by neuroticism (43-57%), while resilience mediated the association in the opposite direction (37-40%). For both self-reported and clinical diagnoses, the genetic risk for depression was independently mediated by neuroticism and resilience. Findings suggest polygenic risk for depression increases vulnerability for self-reported and clinical depression through independent effects on increased neuroticism and reduced psychological resilience. In addition, two partially independent mechanisms - neuroticism and resilience - may form part of the pathway of vulnerability to depression.
Highlights
Major depressive disorder (MDD) is a pervasive and disabling psychiatric condition characterised by periods of low mood and anhedonia, with an estimated lifetime prevalence of 16% (Levine et al 2014)
Using structural equation modelling, we examined if neuroticism mediates the relationship between Polygenic risk scores (PRS) for MDD and both clinical and self-reported MDD to increase the risk for the disorder, and if resilience would mediate in the opposite direction
A 1 S.D. increase in genetic liability to depression was associated with an increased likelihood of clinical depression by an odds ratios (ORs) of 1.20 [(95% confidence intervals (CIs) 1.11–1.31), p < 0.001]
Summary
Major depressive disorder (MDD) is a pervasive and disabling psychiatric condition characterised by periods of low mood and anhedonia, with an estimated lifetime prevalence of 16% (Levine et al 2014). Reports suggest that resilience reduces risk for depression in individuals with high genetic loading for the disorder (Wichers et al 2007; Wichers et al 2008; Geschwind et al 2010). Current research suggests a positive association between neuroticism and MDD; self-reported resilience and depression show a negative association. In a series of moderation analyses, we investigated whether the association between PRS for MDD and clinical and self-reported depression (Sullivan & MDD Working Group of the Psychiatric Genomics Consortium, 2012; Levine et al 2014) was moderated by neuroticism or resilience. Using structural equation modelling, we examined if neuroticism mediates the relationship between PRS for MDD and both clinical and self-reported MDD to increase the risk for the disorder, and if resilience would mediate in the opposite direction.
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