Association between Systemic Lupus Erythematosus and Primary Hypothyroidism: evidence from complementary genetic methods

Abstract Introduction Systemic lupus erythematosus (SLE) and hypothyroidism often coexist in observational studies; however, the causal relationship between them remains controversial. Methods Complementary genetic approaches, including genetic correlation, Mendelian randomization (MR) and colocalization analysis, were conducted to assess the potential causal association between SLE and primary hypothyroidism using summary statistics from large-scale genome-wide association studies (GWASs). The association between SLE and thyroid-stimulating hormone (TSH) was further analyzed to help interpret the findings. In addition, findings were verified using a validation dataset, as well as through different MR methods with different model assumptions. Results The linkage disequilibrium score regression revealed a shared genetic structure between SLE and primary hypothyroidism, with the significant genetic correlation estimated to be 0.2488 (p = 6.00 × 10−4). MR analysis with the inverse variance weighted (IVW) method demonstrated a bidirectional causal relationship between SLE and primary hypothyroidism. The odds ratio (OR) of SLE on primary hypothyroidism was 1.037 (95% CI, 1.013-1.061; p = 2.00 × 10−3) and that of primary hypothyroidism on SLE was 1.359 (95% CI, 1.217-1.520; p < 0.001). The OR of SLE on TSH was 1.007 (95% CI, 1.001-1.013; p = 0.032) .However, TSH was not causally associated with SLE (p = 0.152). Similar results were found using different MR methods. In addition, colocalization analysis suggested that shared causal variants existed between SLE and primary hypothyroidism. The results of the validation analysis indicated a bidirectional causal relationship between SLE and primary hypothyroidism, as well as shared loci. Conclusion In summary, a bidirectional causal relationship between SLE and primary hypothyroidism was observed with complementary genetic approaches.