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Genetic heterogeneity and subtypes of major depression
Open accessPublished version of a preprint
Abstract
Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment, and postpartum depression; N ~ 3000-47000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders/traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (-0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.
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“Several studies have explored the association between the onset age and HDRS-17 score in patient with MDD, but the results were inconsistent [71-74].”
From Mapping neurophysiological subtypes of major depressive disorder using normative models of the functional connectome (2023) · cites this paper as [72]
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Cites
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The UK Biobank resource with deep phenotyping and genomic data
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Szymkowicz, S. M., Gerlach, A., Homiack, D., & Taylor, W. D. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02464-9 · Cited by 234
The genetic basis of major depressive disorder
Flint, J. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-01957-9 · Cited by 156
Sun, X., Sun, J., Lu, X., Dong, Q., Zhang, L., Wang, W., Liu, J., Ma, Q., Wang, X., Wei, D., et al. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.05.021 · Cited by 129
Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression
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Self-citationvon Mücke-Heim, I.-A., Urbina-Treviño, L., Bordes, J., Ries, C., Schmidt, M. V., & Deussing, J. M. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01762-w · Cited by 53
Metadata
- Authors
- Nguyen, T.-D., Harder, A., Xiong, Y., Kowalec, K., Hägg, S., Cai, N., Kuja-Halkola, R., Dalman, C., Sullivan, P. F., & Lu, Y.
- Affiliations
- Karolinska Institutet (SE)
- Helmholtz Munich (DE)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Lu, Yi
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2022-01-08
- Volume
- 27
- Issue
- 3
- Pages
- 1667-1675
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC9106834
- OpenAlex
- W4206146668
- Cited by
- 129
- References
- 48
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 31 · 2023: 23 · 2022: 10
- FWCI
- 15.37
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Site cant be reached (submittedVersion, other-oa)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- University of Manitoba
- European Commission (HORIZON2020, 610307, 847776)
- Vetenskapsrådet (05973, U01-MH-109528, R01 MH077139, 2018-, 201805973, D0886501)
- Medical Research Council (MC_PC_17228)
- Uppsala Multidisciplinary Center for Advanced Computational Science
- National Institute of Mental Health (R01MH077139, U01MH109528, MH123724, R01MH123724, U01 MH109528 and R01 MH077139, MH077139, R01MH124871)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- major depressive disorder, genetic heterogeneity, depression subtypes, SNP heritability, genetic correlation, atypical depression, early-onset depression, recurrent depression, suicidality, postpartum depression, anxiety comorbidity, body mass index, mental illness
- MeSH terms
- Depression, Major Depressive Disorder, Female, Humans, Genetic Heterogeneity, Genome-Wide Association Study, Suicidal Ideation
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