Shared genetic etiology between hypothyroidism and complex diseases: a large-scale genome-wide cross-trait analysis

Hypothyroidism is a common condition of thyroid hormone insufficiency, and there is growing evidence of its link with additional diseases. It remains unclear whether these associations share a common genetic architecture. To address this gap, by leveraging summary-level genetic data from the UK Biobank of hypothyroidism and the FinnGen study of three complex diseases (sarcoidosis, chronic sinusitis, and interstitial lung disease (ILD) endpoints), we evaluated their shared genetic etiology. A significant genetic correlation was found between hypothyroidism and the three diseases. Cross-trait analyses utilizing the MTAG and CPASSOC models revealed 12, 2, and 12 shared loci between hypothyroidism and chronic sinusitis, ILD endpoints, and sarcoidosis, respectively. The SNP heritability enrichment analysis across 37 tissues and 136 cell types at the single-cell level identified candidate tissues and cell types that were shared by the diseases. Interestingly, we found a positive genetic relationship between these four diseases and central memory CD4+ T cells in the blood, supported by strong colocalization evidence (posterior probability >0.9). Mendelian randomization and colocalization analysis showed a link between hypothyroidism and sarcoidosis with two genes (DOCK6 and CD226) in the blood. Furthermore, among the hypothyroidism-driven plasma proteins, RIPK2 was identified as a potentially actionable mediator of hypothyroidism’s effect on ILD endpoints. Overall, our findings contribute to improving our understanding of the molecular basis of these diseases’ intricate relationships, as well as providing insights toward disease prevention and comorbidity management.