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.