Cited by 129Genetic Associations and EpidemiologyTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

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Genetic heterogeneity and subtypes of major depression

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Nguyen, Thuy-Dung, Harder, Arvid, Xiong, Ying, Kowalec, Kaarina, Hägg, Sara, Cai, Na, Kuja-Halkola, Ralf, Dalman, Christina, Sullivan, Patrick F., Lu, Yi·2022·Molecular Psychiatry

DOI 10.1038/s41380-021-01413-6PMC PMC9106834

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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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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: Nguyen, Thuy-Dung
Harder, Arvid
Kowalec, Kaarina
Hägg, Sara
Cai, Na
Kuja-Halkola, Ralf
Dalman, Christina
Sullivan, Patrick F.
Lu, Yi
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2022-01-08
Volume: 27
Issue: 3
Pages: 1667-1675
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/s41380-021-01413-6
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: cc-by-nc-nd
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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Genetic heterogeneity and subtypes of major depression

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