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. 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 data set, 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 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.

Keywords: Mendelian randomization; colocalization; genetic correlation; primary hypothyroidism; systemic lupus erythematosus.