Genetic Adaptation to Tibetan High Altitude and Hepatocellular Cancer Risk: Integrative Bidirectional Mendelian Randomization and Single-Cell RNA Sequencing Analysis

Abstract

Nimadeji, Yanna Cai, and Na Gao. Genetic adaptation to Tibetan high altitudes and hepatocellular cancer risk: integrative bidirectional Mendelian randomization and single-cell RNA sequencing analysis. High Alt Med Biol. 00:00–00, 2025.

Background:

The unique genetic adaptations of Tibetans to high-altitude environments may influence disease susceptibility, including hepatocellular carcinoma (HCC).

Methods:

We employed bidirectional two-sample Mendelian randomization (MR) using genome-wide association study summary statistics: high-altitude adaptation (HAA) data from Tibetan/non-Tibetan East Asians (n = 10,295) and HCC data from BioBank Japan (1,866 cases/195,745 controls). Instrumental variables were selected via genome-wide significance (p < 5 × 10⁻⁸), with inverse variance-weighted random-effects models as primary analysis. MR-Egger regression analysis and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global analysis were used to evaluate the pleiotropic effect. Single-cell RNA sequencing from the Hepatocellular Carcinoma Database identified HAA-related differentially expressed genes (DEGs) in HCC tissues, followed by functional enrichment analysis.

Results:

MR results demonstrated HAA as a causal risk factor for HCC (odds ratio = 2.15 × 10², 95% confidence interval = 1.57–2.96 × 10⁴, p = 0.032), with no reverse causality. Single-cell analysis revealed 23 HAA-associated DEGs in HCC, enriched in immune regulation, DNA metabolism, and cell growth pathways. Notably, genes such as EPAS1 and GCH1; Guanosine triphosphate, GTP, previously linked to Tibetan HAA, were found to be differentially expressed in HCC tissues.

Conclusion:

This study provides statistical and genetic evidence that HAA is a causal risk factor for HCC in Tibetans. The identification of HAA-related genes in HCC tissues offers new insights for targeted prevention and treatment strategies in Tibetan populations.