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Genetics, epigenetics, and neurobiology of childhood-onset depression: an umbrella review

Molecular Psychiatry (2023)Cite this article

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Abstract

Depression is a serious and persistent psychiatric disorder that commonly first manifests during childhood. Depression that starts in childhood is increasing in frequency, likely due both to evolutionary trends and to increased recognition of the disorder. In this umbrella review, we systematically searched the extant literature for genetic, epigenetic, and neurobiological factors that contribute to a childhood onset of depression. We searched PubMed, EMBASE, OVID/PsychInfo, and Google Scholar with the following inclusion criteria: (1) systematic review or meta-analysis from a peer-reviewed journal; (2) inclusion of a measure assessing early age of onset of depression; and (3) assessment of neurobiological, genetic, environmental, and epigenetic predictors of early onset depression. Findings from 89 systematic reviews of moderate to high quality suggest that childhood-onset depressive disorders have neurobiological, genetic, environmental, and epigenetic roots consistent with a diathesis-stress theory of depression. This review identified key putative markers that may be targeted for personalized clinical decision-making and provide important insights concerning candidate mechanisms that might underpin the early onset of depression.

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Fig. 1
Fig. 2: Neurobiological associations with early onset depression.
Fig. 3: Genetic associations with early onset depression.
Fig. 4: Environmental associations with early onset depression.
Fig. 5: Epigenetic associations with early onset depression.

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Data availability

All systematic reviews and literature used as source data for the umbrella review are available at Pubmed (including MEDLINE), PsycInfo, EMBASE, and Google Scholar. All datasets used for evaluation of results are clearly identified and available in the published article and its supplementary information files.

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Acknowledgements

Preparation of this paper was facilitated by National Institutes of Health Grant R01MH MH106581 to MKS, R37MH101495 to IHG and NSF DGE-213989 to AJG.

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Authors and Affiliations

  1. Stanford University, Stanford, CA, USA

    Manpreet K. Singh, Christopher Stave & Ian H. Gotlib

  2. Washington University, St. Louis, MO, USA

    Aaron J. Gorelik

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Contributions

MKS and CS conceptualized the search strategy and executed the umbrella review. MKS and AJG contributed to the manual tagging of abstracts, full text screening and review, extraction, categorization, and synthesis, and appraisal of quality, bias, and heterogeneity. MKS, AJG, CS and IHG contributed to writing and revision of the manuscript. MKS contributed to visualizations.

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Correspondence to Manpreet K. Singh.

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Competing interests

MKS has received research support from Stanford’s Maternal Child Health Research Institute and Stanford’s Department of Psychiatry and Behavioral Sciences, National Institute of Mental Health, National Institute of Aging, Patient Centered Outcomes Research Institute, Johnson and Johnson, and the Brain and Behavior Research Foundation. She has been on the advisory board for Sunovion and Skyland Trail, is a consultant for Johnson and Johnson, Alkermes, Neumora, AbbVie, Karuna Therapeutics, Inc., Boehringer-Ingelheim, and Alto Neuroscience. She receives honoraria from the American Academy of Child and Adolescent Psychiatry, and royalties from American Psychiatric Association Publishing and Thrive Global. No other authors disclose any conflicts of interest.

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Singh, M.K., Gorelik, A.J., Stave, C. et al. Genetics, epigenetics, and neurobiology of childhood-onset depression: an umbrella review. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02347-x

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