Youth depression: An overview of genetic findings and the challenge of heterogeneity

Thapar, Anita ORCID: https://orcid.org/0000-0002-3689-737X, Oginni, Olakunle, Dennison, Charlotte A. ORCID: https://orcid.org/0000-0002-7493-2041 and Rice, Frances ORCID: https://orcid.org/0000-0002-9484-1729 2025. Youth depression: An overview of genetic findings and the challenge of heterogeneity. Journal of Affective Disorders , p. 120049. 10.1016/j.jad.2025.120049

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Abstract

Background Depression in youth is common but a highly heterogenous disorder. In the last decade there have been much larger family and twin studies as well as molecular genetic advances. However, although considered as a unitary diagnostic concept, depression is extremely variable in terms of its definition, measurement, age-at-onset, clinical antecedents or comorbidities, and long-term outcomes. Method In this narrative review, we summarise findings on the genetics of youth depression, as well as consider the many challenges around heterogeneity. Results Youth depression is familial, modestly heritable, and inter-generational transmission appears to be explained by rearing as well as genetic contributions. Non-shared environmental factors are a major contributor and gene-environment correlation is especially important for youth depression. Although there is overlap between youth and adult depression in genetic liability, youth-onset depressive disorder may represent a distinct subtype in terms of its genetic profile. Familial loading and heritability are higher when youth-onset depressive disorder is recurrent, chronic and more severe than when depression is milder and defined more broadly. Polygenic scores and pharmacogenetic testing are not ready for clinical use. There are many inconsistencies in findings that may be explained by heterogeneity. Limitations There are no large genome-wide association studies of youth depression. The lack of diversity in ancestry is a problem. Conclusion We highlight that future genetic studies of youth depression need to consider more careful harmonisation of definitions, measures, take into account recurrence or chronicity and severity of depression as well as include more diverse populations.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Elsevier
ISSN:	0165-0327
Date of First Compliant Deposit:	18 August 2025
Date of Acceptance:	10 August 2025
Last Modified:	18 Aug 2025 14:15
URI:	https://orca.cardiff.ac.uk/id/eprint/180515

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