| Title: | Comorbidity alters the genetic relationship between anxiety disorders and major depression |
| Journal: | Biological Psychiatry |
| Published: | 8 May 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42107849/ |
| DOI: | https://doi.org/10.1016/j.biopsych.2026.04.026 |
| URL: | https://www.biologicalpsychiatryjournal.com/article/S0006-3223(26)01227-8/pdf |
Publication 20060
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Abstract
BACKGROUND: The extensive genetic overlap between anxiety disorders (ANX) and major depression (MD) may partly reflect inclusion of comorbid cases in genome-wide association studies (GWAS). We investigated this genetic relationship between ANX and MD with and without mutual comorbidity.</p>
METHODS: Using UK Biobank, we performed disorder-specific GWAS for ANX-only (cases/controls = 9,980/179,442) and MD-only (cases/controls = 15,301/179,038) and derived polygenic risk scores (PRS). In the Norwegian Mother, Father, and Child Cohort (MoBa), we tested associations of PRS with MD-only (N=7,486), ANX-only (N=1,992), and comorbid (ANX-MD) (N=3,468) and controls (N=85,851). PRS associations with anxiety and depression symptoms were tested in MoBa (N=54,862). GWAS including comorbid cases (MD-comorbid or ANX-comorbid) were used for comparison. Genetic correlations were compared by comorbidity status, and Mendelian randomization was employed to assess causal relationships.</p>
RESULTS: MD-comorbid and ANX-comorbid PRS showed stronger association with ANX-MD cases than with their primary disorders, MD-only (Z=-2.82; Padjusted=0.01) and ANX-only (Z=-2.36; Padjusted=0.03), respectively. MD-only PRS was more strongly associated with MD-only than with ANX-only cases (Z=3.63; Padjusted=6.9e-04). The genetic correlation was lower between ANX-only and MD-only (rg=0.53, SE=0.11) than between ANX-comorbid and MD-comorbid (rg=0.91, SE=0.01). Bidirectional causal effects observed in comorbidity-inclusive analyses were attenuated to null when comorbid states were excluded. Gene sets of MD-comorbid, ANX-comorbid, and MD-only, but not of ANX-only, were enriched for the immune regulation pathway - interleukin-21 production.</p>
CONCLUSIONS: The genetic distinction between ANX and MD becomes more pronounced when comorbid cases are excluded. The findings underscore the importance of disorder-specific genetic studies for advancing precision medicine.</p>
16 Authors
- Markos Tesfaye
- Alexey Shadrin
- Nadine Parker
- Piotr Jaholkowski
- Pravesh Parekh
- Gleda Kutrolli
- Viktoria Birkenæs
- Nora R Bakken
- Helga Ask
- Guy Hindley
- Oleksandr Frei
- Srdjan Djurovic
- Anders M Dale
- Olav B Smeland
- Kevin S O'Connell
- Ole A Andreassen
1 Application
| Application ID | Title |
|---|---|
| 27412 | Boosting the power of GWAS using novel statistical tools |
Enabling scientific discoveries that improve human health