Shared genetic architecture between hypothyroidism and rheumatoid arthritis: A large-scale cross-trait analysis

In recent years, mounting evidence has indicated a co-morbid relationship between hypothyroidism and rheumatoid arthritis (RA), however, the shared genetic factors underlying this association remain unclear. This study aims to investigate the common genetic architecture between hypothyroidism and RA. Genome-wide association study (GWAS) summary statistics from recently published studies were utilized to examine the genetic correlation, shared genetic loci, and potential causal relationship between hypothyroidism and RA. Statistical methods included linkage disequilibrium score regression (LDSC), high-definition likelihood (HDL), cross-trait meta-analyses, colocalization analysis, multi-marker analysis of genomic annotation (MAGMA), tissue-specific enrichment analysis (TSEA), functional enrichment analysis, and latent causal variable method (LCV). Our study demonstrated a significant genetic correlation between hypothyroidism and RA(LDSC:rg=0.3803,p=7.23e-11;HDL:rg=0.3849,p=1.02e-21). Through cross-trait meta-analysis, we identified 1035 loci, including 43 novel genetic loci. By integrating colocalization analysis and the MAGMA algorithm, we found a substantial number of genes, such as PTPN22, TYK2, and CTLA-4, shared between the two diseases, which showed significant enrichment across 14 tissues. These genes were primarily associated with the regulation of alpha-beta T cell proliferation, positive regulation of T cell activation, positive regulation of leukocyte cell-cell adhesion, T cell receptor signaling pathway, and JAK-STAT signaling pathway. However, our study did not reveal a significant causal association between the two diseases using the LCV approach. Based on these findings, there is a significant genetic correlation between hypothyroidism and RA, suggesting a shared genetic basis for these conditions.