Characterizing Developmental Trajectories and the Role of Neuropsychiatric Genetic Risk Variants in Early-Onset Depression
Open accessAbstract
Importance: Depression often first manifests in adolescence. Thereafter, individual trajectories vary substantially, but it is not known what shapes depression trajectories in youth. Adult studies suggest that genetic risk for schizophrenia, a psychiatric disorder with a neurodevelopmental component, may contribute to an earlier onset of depression. Objective: To test the hypothesis that there are distinct trajectories of depressive symptoms and that genetic liability for neurodevelopmental psychiatric disorders (eg, schizophrenia, attention deficit/hyperactivity disorder [ADHD]), as well as for major depressive disorder (MDD), contribute to early-onset depression. Design, Setting, and Participants: The Avon Longitudinal Study of Parents and Children is an ongoing, prospective, longitudinal, population-based cohort that has been collecting data since September 6, 1990, including data on 7543 adolescents with depressive symptoms at multiple time points. The present study was conducted between November 10, 2017, and August 14, 2018. Main Outcomes and Measures: Trajectories based on self-reported depressive symptoms dichotomized by the clinical cutpoint; MDD, schizophrenia, and ADHD polygenic risk score (PRS) were predictors. Results: In 7543 adolescents with depression data on more than 1 assessment point between a mean (SD) age of 10.64 (0.25) years and 18.65 (0.49) years (3568 [47.3%] male; 3975 [52.7%] female), 3 trajectory classes were identified: persistently low (73.7%), later-adolescence onset (17.3%), and early-adolescence onset (9.0%). The later-adolescence-onset class was associated with MDD genetic risk only (MDD PRS: odds ratio [OR], 1.27; 95% CI, 1.09-1.48; P = .003). The early-adolescence-onset class was also associated with MDD genetic risk (MDD PRS: OR, 1.24; 95% CI, 1.06-1.46; P = .007) but additionally with genetic risk for neurodevelopmental disorders (schizophrenia PRS: OR, 1.22; 95% CI, 1.04-1.43; P = .01; ADHD PRS: OR, 1.32; 95% CI, 1.13-1.54; P < .001) and childhood ADHD (χ21 = 6.837; P = .009) and neurodevelopmental traits (pragmatic language difficulties: OR, 1.31; P = .004; social communication difficulties: OR, 0.68; P < .001). Conclusions and Relevance: The findings of this study appear to demonstrate evidence of distinct depressive trajectories, primarily distinguished by age at onset. The more typical depression trajectory with onset of clinically significant symptoms at age 16 years was associated with MDD genetic risk. The less-common depression trajectory, with a very early onset, was particularly associated with ADHD and schizophrenia genetic risk and, phenotypically, with childhood ADHD and neurodevelopmental traits. Findings are consistent with emerging evidence for a neurodevelopmental component in some cases of depression and suggest that the presence of this component may be more likely when the onset of depression is very early.
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An analysis of WMH data showed that a history of depression as of the age of completing schooling predicted current (at the time of interview) unemployment and work disability.
“For example, an analysis of WMH data showed that a history of depression as of the age of completing schooling predicted current (at the time of interview) unemployment and work disability. 226”
From Time for united action on depression: a Lancet–World Psychiatric Association Commission (2022) · cites this paper as [226]
The loading of MD on two factors may reflect biological heterogeneity within MD.
“The loading of MD on two factors may reflect biological heterogeneity within MD, consistent with recent evidence showing that early-onset depression is associated with genetic risk for ADHD and with neurodevelopmental phenotypes (Rice et al., 2019).”
From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Rice et al., 2019
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References 83 · Cited by 167
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- Authors
- Rice, F., Riglin, L., Thapar, A. K., Heron, J., Anney, R., O’Donovan, M. C., & Thapar, A.
- Affiliations
- Cardiff University (GB)
- University of Bristol (GB)
- Corresponding author
- Rice, Frances
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2019-03-01
- Volume
- 76
- Issue
- 3
- Pages
- 306
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC6439821
- OpenAlex
- W2896482483
- Cited by
- 167
- References
- 83
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 17 · 2023: 21 · 2022: 17 · 2021: 32 · 2020: 21 · 2019: 17
- FWCI
- 20.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Explore Bristol Research (submittedVersion, cc-by)
- Funders
- Wellcome Trust (204895/Z/16/Z)
- Medical Research Council (MR/L010305/1, MC_PC_15018, MR/M012964/1, MR/R004609/1, MC_PC_19009)
- National Institute of Mental Health (U01MH109536)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- early-onset depression, adolescent depression, depressive symptom trajectories, polygenic risk score, major depressive disorder, genetic susceptibility, Avon Longitudinal Study of Parents and Children
- MeSH terms
- Adolescent, Attention Deficit Disorder with Hyperactivity, Child, Depression, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Longitudinal Studies, Male, Prospective Studies, Risk Factors, Schizophrenia, Comorbidity, Age of Onset, Disease Progression, Genetic Predisposition to Disease
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