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

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. In this narrative review, we summarise findings on the genetics of youth depression, as well as consider the many challenges around heterogeneity. 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. There are no large genome-wide association studies of youth depression. The lack of diversity in ancestry is a problem. 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. • Youth depression is familial and modestly heritable • Heritability is higher for more severe youth-onset depression that is chronic or recurrent in course. • Inter-generational transmission appears to be explained by rearing as well as genetic contributions. • Non-shared environmental factors and gene-environmental correlation are major contributors • Polygenic scores and pharmacogenetic testing are not ready for clinical use.