Dissecting shared genetic architecture between hypothyroidism and immune-related diseases

Hypothyroidism is a common endocrine disorder characterized by insufficient thyroid hormone production and there are increasing reports of hypothyroidism being associated with a variety of complex diseases. However, whether these associations share a common genetic basis remains unclear. In this study, we investigated the shared genetic architecture underlying hypothyroidism and three immune-related diseases, including sarcoidosis, chronic sinusitis, and interstitial lung disease (ILD) endpoints, using large-scale genome-wide cross-traits analysis. Linkage disequilibrium score regression and genetic covariance analysis revealed significant genetic correlations between hypothyroidism and each of the three diseases. Cross-trait meta-analyses identified 26 shared risk loci between hypothyroidism and other three diseases. Cell-type SNP heritability enrichment analyses highlighted that central memory CD4⁺ T cells in the blood are co-enriched by these four diseases, which was further confirmed by co-localization analysis (posterior probability>0.9). Furthermore, DOCK6 and CD226 were identified as candidate causal genes shared by hypothyroidism and sarcoidosis, while RIPK2 was found as a hypothyroidism-driven plasma protein that may mediate the risk of ILD endpoints. Overall, these findings provide new insights into the shared genetic underpinnings of hypothyroidism and immune-related diseases and offer potential targets for comorbidity risk assessment and therapeutic intervention.