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

Clarke, Toni‐Kim; Navrady, Lauren; Zeng, Yanni; Xia, Charley; Haley, Chris; Campbell, Archie; Navarro, Pau; Amador, Carmen; Adams, Mark; Howard, David M.; Soler, A.; Hayward, Caroline; Thomson, Pippa A.; Smith, Blair H.; Padmanabhan, Sandosh; Hocking, Lynne J.; Hall, Lynsey S.; Porteous, David J.; Deary, Ian J.

doi:10.1101/211896

Cited by 8 publications

(8 citation statements)

References 46 publications

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“…However, importantly, both genetic influences and adoption explain only a small part of individual differences in mental health on the population level, and the difference in genetic risk between adoptees and nonadoptees explained only a small fraction of the adoption effect. Our findings are in line with two recent studies using self-reported trauma measures reporting a small but significant association between major depression PRSs and childhood trauma (21) and between the PRSs for major depression and neuroticism with recent SLE exposure, respectively (36). However, the majority of studies exploring main effects of genetic risk and SLE exposure and their interaction on mental health outcomes did not assess potential gene-environment correlations [e.g., (24,37)].…”

Section: Genetic Differencessupporting

confidence: 89%

Childhood Adoption and Mental Health in Adulthood: The Role of Gene-Environment Correlations and Interactions in the UK Biobank

Lehto

Hägg

et al. 2020

Biological Psychiatry

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BACKGROUND: Being adopted early in life, an indicator of exposure to early-life adversity, has been consistently associated with poor mental health outcomes in adulthood. Such associations have largely been attributed to stressful environments, e.g., exposure to trauma, abuse, or neglect. However, mental health is substantially heritable, and genetic influences may contribute to the exposure to childhood adversity, resulting in potential genetic confounding of such associations. METHODS: Here, we explored associations between childhood adoption and mental health-related outcomes in midlife in 243,797 UK Biobank participants (n adopted = 3151). We used linkage disequilibrium score regression and polygenic risk scores for depressive symptoms, schizophrenia, neuroticism, and subjective well-being to address potential genetic confounding (gene-environment correlations) and gene-environment interactions. As outcomes, we explored depressive symptoms, bipolar disorder, neuroticism, loneliness, and mental health-related socioeconomic and psychosocial measures in adoptees compared with nonadopted participants. RESULTS: Adoptees were slightly worse off on almost all mental, socioeconomic, and psychosocial measures. Each standard deviation increase in polygenic risk for depressive symptoms, schizophrenia, and neuroticism was associated with 6%, 5%, and 6% increase in the odds of being adopted, respectively. Significant genetic correlations between adoption status and depressive symptoms, major depression, and schizophrenia were observed. No evidence for gene-environment interaction between genetic risk and adoption on mental health was found. CONCLUSIONS: The association between childhood adoption and mental health cannot fully be attributed to stressful environments but is partly explained by differences in genetic risk between adoptees and those who have not been adopted (i.e., gene-environment correlation).

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Section: Genetic Differencessupporting

confidence: 89%

Childhood Adoption and Mental Health in Adulthood: The Role of Gene-Environment Correlations and Interactions in the UK Biobank

Lehto

Hägg

et al. 2020

Biological Psychiatry

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“…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 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 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.…”

Section: Discussionmentioning

confidence: 99%

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

Lasconi¹,

Pahl²,

Cousminer³

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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IBD genetic risk profile Non IBD genetic risk profile Dysfunctional stress responses STRESS Flares Functional stress responses SUMMARY Inflammatory bowel disease is associated with stress and depression. These 2 comorbidities are influenced by the hypothalamus. Integrating our 3-dimensional genomic data with publicly available genome-wide association study data, our results implicate a subset of inflammatory bowel disease loci conferring their effect via the hypothalamus. Our findings warrant further investigation.

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“…However, the now established genetic overlap between stressful life events and major depressive disorder suggests that their relationship may not be directionally causal but a consequence of common genetic effects that influence both. 47 Nonetheless, most of the stressors in the checklist we used are likely independent events (i.e., beyond the control of the child); the genetic overlap between major depressive disorder and independent life events is lower than for dependent life events 47,48 (such as relationship problems or job loss, that may be, in part, the result of a person's own behaviour).…”

Section: Discussionmentioning

confidence: 99%

Prenatal and childhood adverse life events, inflammation and depressive symptoms across adolescence

Flouri

Francesconi

Midouhas

2020

Journal of Affective Disorders

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Background: No study has investigated the role of inflammation in explaining the association between early exposures to adverse life events and depressive symptoms in adolescence. Method: Using data from the Avon Longitudinal Study of Parents and Children, we tested if inflammatory markers [serum C-reactive protein (CRP) and interleukin 6 (IL-6)] at age 9 years mediated the association between adverse life events, measured separately for the prenatal (since the beginning of pregnancy) and the childhood (ages 0-9 years) periods, and the development of depressive symptoms at ages 10-17 years. Data (n=4,263) were analysed using mediation analysis in a latent growth curve modelling framework. Results: Depressive symptoms at the beginning of adolescence (age 10) were associated with the number of prenatal events, the number of events around birth and the increase in events over time in childhood (ages 0-9), even after adjustment for confounders. IL-6 partially mediated the association between increasing exposure to events over time in childhood and depressive symptoms at the beginning of adolescence. IL-6 did not mediate any other association between events and symptoms. There was no evidence for mediation by CRP, which was generally unrelated to events. Limitations: The small size of the mediation effect and the robust direct effects of events prenatally and around birth suggest there are multiple routes from early stressors to adolescent depression. Conclusions: In the general adolescent population, increasing exposure to psychosocial stressors over time during childhood is associated with the early onset of depressive symptoms, partly via increasing levels of plasma IL-6.

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

Cited by 8 publications

References 46 publications

Childhood Adoption and Mental Health in Adulthood: The Role of Gene-Environment Correlations and Interactions in the UK Biobank

Childhood Adoption and Mental Health in Adulthood: The Role of Gene-Environment Correlations and Interactions in the UK Biobank

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

Prenatal and childhood adverse life events, inflammation and depressive symptoms across adolescence

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