| Title: | Genetic heterogeneity affects the risk of incident depression, comorbidity, and response to environment: A prospective trajectory study |
| Journal: | Psychological Medicine |
| Published: | 22 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42324796/ |
| DOI: | https://doi.org/10.1017/s0033291726104140 |
| URL: | ~Ehttps://www.cambridge.org/core/services/aop-cambridge-core/content/view/A680C90F7695EE3192FE6024A0D6A2A7/S0033291726104140a.pdf/div-class-title-genetic-heterogeneity-affects-the-risk-of-incident-depression-comorbidity-and-response-to-environment-a-prospective-trajectory-study-div.pdf~ |
Publication 20583
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Abstract
BACKGROUND: Depression exhibits significant heterogeneity in its genetic underpinnings. The role of genetic components in the development of depression and its comorbidities remains insufficiently explored.</p>
METHODS: First, depression risk loci from a large-scale genome-wide meta-analysis were annotated to Gene Ontology (GO) terms by functional enrichment. GO-based polygenic risk scores (GO-PRS) were then calculated for individuals in the UK Biobank. Principal component analysis (PCA) was applied for dimensionality reduction, followed by cluster analysis to identify genetic subtypes of depression. Multistate models were applied to assess the impact of genetic patterns on the trajectory from healthy status to incident depression, and depression to 26 subsequent diseases, as well as the associations between environmental factors and disease trajectories across genetic subtypes.</p>
RESULTS: Participants were categorized into three genetic subtypes: immune-dominant, neuro-dominant, and comprehensive-risk. Significant differences in risk of depression and subsequent diseases, and susceptibility to environmental factors were observed across subtypes. Comprehensive-risk subtype showed higher risks of depression compared to immune-dominant (HR: 1.10, 95% CI: 1.05-1.15) and neuro-dominant subtype (HR: 1.12, 95% CI: 1.08-1.16). Comprehensive-risk subtype exhibited higher risks of transition from depression to subsequent diseases, such as anemia compared to immune-dominant subtype, and diseases of the digestive system compared to neuro-dominant subtype. Environmental factors were more strongly associated with the transition from depression to subsequent diseases in immune-dominant and comprehensive-risk subtypes, including cardiovascular, respiratory, and metabolic diseases.</p>
CONCLUSIONS: Our findings highlight the genetic heterogeneity of depression and comorbidities, and shed light on how genetic components modulate responses to environmental factors.</p>
18 Keywords
- Aged
- Comorbidity
- Depression
- Depressive Disorder
- Female
- Gene-Environment Interaction
- Genetic Heterogeneity
- Genetic Predisposition to Disease
- Genetic Risk Score
- Genome-Wide Association Study
- Humans
- Incidence
- Male
- Middle Aged
- Prospective Studies
- Risk Factors
- UK Biobank
- United Kingdom
12 Authors
- Chuyu Pan
- Shiqiang Cheng
- Xin Qi
- Bolun Cheng
- Jin Feng
- Meijuan Kang
- Li Liu
- Xuena Yang
- Yan Wen
- Yumeng Jia
- Huan Liu
- Feng Zhang
1 Application
| Application ID | Title |
|---|---|
| 46478 | Multi-omics integrative studies of common psychiatric disorders and skeletal disorders |
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