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<p>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 (r<sub>g</sub> = 0.14, P = 2.96 × 10<sup>−9</sup>) 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>

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Shared genetic architecture and pathways linking major depressive disorder and autoimmune thyroid disease: insights from common and rare variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月1日

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  • 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

摘要

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.