Genetic risk of major depressive disorder: the moderating and mediating effects of neuroticism and psychological resilience on clinical and self-reported depression
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Background: 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. Methods: 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. Results: 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. Conclusions: 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.
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Resilience is negatively correlated with anxiety and depression, suggesting it may protect against these conditions by buffering risk factors.
“Research shows resilience is negatively correlated with anxiety and depression,, suggesting it may protect against these conditions by buffering risk factors [37–43].”
From The prospective association of adolescent loneliness and low resilience with anxiety and depression in young adulthood: The HUNT study (2025) · cites this paper as [42]
The Results (Moderation; page not provided) report an inverse association between resilience and clinical and self-reported depression. The paper does not establish the claimed association with anxiety. It also found no resilience-by-genetic-risk interaction for depression, although its Discussion suggests resilience may mitigate genetic risk through mediation. (LLM, conf=0.87)
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- Authors
- Navrady, L. B., Adams, M. J., Chan, S. W. Y., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Ritchie, S. J., & McIntosh, A. M.
- Affiliations
- Royal Edinburgh Hospital (GB)
- University of Edinburgh (GB)
- Western General Hospital (GB)
- Corresponding author
- Navrady, L. B.
- Venue
- Psychological Medicine
- Publisher
- Cambridge University Press (CUP)
- Published
- 2017-11-29
- Volume
- 48
- Issue
- 11
- Pages
- 1890-1899
- ISSN
- 0033-2917 (ISSN-L)
- 1469-8978
- PMC
- PMC6088772
- OpenAlex
- W2884339004
- Cited by
- 62
- References
- 21
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 10 · 2019: 12 · 2018: 2 · 2017: 1
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Psychological Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Scopus (Elsevier) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (104036/Z/14/Z, 104036)
- Scottish Government (CZD/16/6)
- Scottish Funding Council (HR03006)
- Dr Mortimer and Theresa Sackler Foundation
- Chief Scientist Office, Scottish Government Health and Social Care Directorate (HR03006, CZD/16/6)
- Medical Research Council (MR/K026992/1)
- National Institute of Mental Health (U01MH109536)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- major depressive disorder, polygenic risk score, neuroticism, psychological resilience, genetic risk, mediation, moderation, self-reported depression, personality traits, depression vulnerability
- MeSH terms
- Neuroticism, Adult, Depressive Disorder, Major, Major Depressive Disorder, Female, Humans, Male, Risk, Scotland, Genetic Predisposition to Disease, Multifactorial Inheritance, Resilience, Psychological, Self Report
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