Genome-wide association study reveals acute mountain sickness susceptibility in Chinese population

Acute mountain sickness (AMS) is a major health challenge in high-altitude environments, yet its genetic underpinnings, particularly in the Chinese population, remain poorly characterized. We conducted a genome-wide association study (GWAS) on 156 AMS patients and 313 controls in Chinese population, revealing four novel suggestive single nucleotide polymorphisms (SNPs) (P < 1 × 10^- 5). Among these four SNPs, two SNPs (rs1424442 and rs2246690) were successfully replicated in an independent cohort (P < 0.05), which contains 214 AMS patients and 196 controls. We provide functional insights for these two SNPs: the rs1424442-C allele is implicated in AMS susceptibility potentially by upregulating BPGM expression, thereby altering oxygen release and increasing red blood cell count (RBC) along with hemoglobin (HGB) concentration; while the rs2246690-A allele is associated with reduced UHRF2 expression in the prefrontal cortex and cognitive delay, offering a direct genetic link to AMS-related neurological impairment. Integrative analyses further substantiated the involvement of immune and gastrointestinal systems in AMS pathogenesis. Our work not only reports new genetic associations but also proposes specific molecular mechanisms, providing a valuable foundation for understanding AMS and developing future interventions.