Joint Analysis of Genetic Correlation, Mendelian Randomization and Colocalization Highlights the Bi-Directional Causal Association Between Hypothyroidism and Primary Biliary Cirrhosis

Background: Hypothyroidism and primary biliary cirrhosis (PBC) are often co-existed in observational epidemiological studies. However, the causal relationship between them remains unclear. Methods: Genetic correlation, Mendelian randomization (MR) and colocalization analysis were combined to assess the potential causal association between hypothyroidism and PBC by using summary statistics from large-scale genome-wide association studies. Various sensitivity analyses had been conducted to assess the robustness and the consistency of the findings. Results: The linkage disequilibrium score regression demonstrated significant evidence of shared genetic architecture between hypothyroidism and PBC, with the genetic correlation estimated to be 0.117 (p = 0.006). The OR of hypothyroidism on PBC was 1.223 (95% CI, 1.072-1.396; p = 2.76 × 10^-3) in MR analysis with inverse variance weighted (IVW) method. More importantly, the results from other 7MR methods with different model assumptions, were almost identical with that of IVW, suggesting the findings were robust and convincing. On the other hand, PBC was also causally associated with hypothyroidism (OR, 1.049; 95% CI, 1.010-1.089; p = 0.012), and, again, similar results can also be obtained from other MR methods. Various sensitivity analyses regarding the outlier detection and leave-one-out analysis were also performed. Besides, colocalization analysis suggested that there existed shared causal variants between hypothyroidism and PBC, further highlighting the robustness of the results. Conclusion: Our results suggest evidence for the bi-directional causal association between hypothyroidism and PBC, which may provide insights into the etiology of hypothyroidism and PBC as well as inform prevention and intervention strategies directed toward both diseases.