| Title: | Shared genetic architecture and pathways linking major depressive disorder and autoimmune thyroid disease: insights from common and rare variants |
| Journal: | Translational Psychiatry |
| Published: | 1 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42225622/ |
| DOI: | https://doi.org/10.1038/s41398-026-04146-8 |
| URL: | https://www.nature.com/articles/s41398-026-04146-8_reference.pdf |
Publication 19846
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Abstract
Major depressive disorder (MDD) and autoimmune thyroid disease (AITD) frequently co-occur, yet the genetic factors underlying their comorbidity remain unclear. We performed a population-matched cohort study from the UK Biobank to evaluate the phenotypic association between MDD and AITD. Genetic correlation, causal relationships, and pleiotropic loci/genes shared between the diseases were assessed based on common variants using genome-wide association study (GWAS) summary statistics, complemented by individual-level validation through polygenic risk score analysis. We additionally performed an exome-wide association analysis using the UK Biobank 450k whole-exome sequencing (WES) release to identify disease-specific risk genes from rare variants. Findings from common and rare variants were integrated and subjected to pathway enrichment, protein-protein interaction (PPI) and transcription factor (TF) analyses to locate functional modules. In the cohort study, MDD and AITD were associated with a 2.8-fold increased risk of developing the other condition. We confirmed a modest but statistically significant positive genetic correlation (rg = 0.14, P = 2.96 × 10−9) and confirmed the absence of a direct causal relationship. Integrative pleiotropy analyses identified 14 pleiotropic loci mapped to 58 shared genes. Gene ontology, TF enrichment and PPI analyses of disease-specific and shared genes revealed that the genetic signals converge on shared modules involving T-cell receptor signaling, thyroid hormone metabolic process and neurodegeneration, prioritized by key immune-inflammatory and neuro-developmental regulators. Our findings provide a molecular framework for MDD-AITD comorbidity, highlighting specific pathways as potential targets for integrated therapeutic strategies.</p>
16 Authors
- Siyi Liu
- Yu Zeng
- Liling Xiao
- Yulu Wu
- Can Hou
- Huazhen Yang
- Menghan Wei
- Yiguo Tang
- Yunqi Huang
- Yunjia Liu
- Qianshu Ma
- Yubing Yin
- Mengting Zhang
- Yang Chen
- Huan Song
- Qiang Wang
1 Application
| Application ID | Title |
|---|---|
| 54803 | Deciphering complex traits - phenotypic and genetic associations between traits in the UK Biobank Cohort |
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