Using Mendelian Randomization to Dissect the Relationship Between High-Altitude Adaptation and Liver Diseases/Traits

Wu, Tianzhun, Ruofan Li, Song, Li Xu, Chaofan Shi, Juanjuan Liu, Xing Gao, Shilin Huang, Shizhou Li, Dandan Zeng, Wenfeng Luo, Yan Lin, Jiazhou Ye, Minggen Hu, and Rong Liang. Using Mendelian randomization to dissect the relationship between high-altitude adaptation and liver diseases/traits. High Alt Med Biol. 00:00-00, 2025. Background: It has been reported that high-altitude adaptation (HAA) and susceptibility to multiple liver diseases/traits differ between individuals at higher altitudes compared to those at lower altitudes. To investigate this association, we conducted a Mendelian randomization study. Methods: To investigate the association between HAA and liver diseases/traits, we utilized genome-wide association studies focusing on East Asian ancestry. Our study included six liver disease-related phenotypes: autoimmune hepatitis, chronic hepatitis B, chronic hepatitis C, acute hepatitis by hepatitis A virus, hepatic cancer, and hepatic bile duct cancer, as well as five liver traits: alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase (GGT), and total bilirubin. A Bonferroni-corrected significance was set at p < 4.55 × 10^-3. Results: Our study identified a significant genetically predicted causal impact of HAA on GGT (odds ratio [OR] = 1.601; 95% confidence interval [CI] = 1.204-2.129; p = 0.0012). Interestingly, the association remained statistically significant even when the causal direction was reversed, with GGT predicting HAA (OR = 1.01; 95% CI = 1.003-1.011; p = 0.0013). Both findings surpassed the Bonferroni-corrected threshold. Conclusion: In conclusion, our study provides suggestive evidence for a potentially causal bidirectional association between HAA and GGT. These novel insights may inform the development of targeted preventive measures and therapeutic interventions for liver diseases and high-altitude adaptation.