Mendelian Randomization Analysis of ITGA2 and ECM1 in Obstructive Sleep Apnea: Genetic and Tissue-Specific Evidence

Purpose Obstructive sleep apnea syndrome (OSA) has a complex etiology and lacks targeted therapies. This study employs Mendelian randomization (MR) to identify druggable targets causally associated with OSA risk, elucidate their molecular mechanisms, and guide the development of precision treatments. Methods Cis-eQTL data for drug-target genes were extracted from the eQTLGen database as exposure variables. Instrumental variables were selected (F > 10, P < 5 × 10⁻⁸, r² < 0.1, FDR < 0.05) to pinpoint candidate genes. Causal effects and functional insights were validated through colocalization (PP.H4 > 0.75), SMR, MetaXcan, and Ph-MR analyses. Results Of 21 candidate genes, ITGA2 and ECM1 were linked to OSA. ITGA2 exhibited a robust effect (MR OR = 1.10, FDR P = 1.85 × 10⁻⁷; SMR P = 0.0002, p_HEIDI = 0.2084), with colocalization evidence for shared genetic control (PP.H4 = 0.778). MetaXcan analysis revealed its expression in the hippocampus and left ventricle (P < 0.05), likely affecting OSA via inflammation and airway fibrosis. ECM1 had a weaker effect (MR OR = 1.16, FDR P = 0.0065; SMR p_HEIDI = 0.0407), with MetaXcan indicating expression across tissues like the hypothalamus and whole blood (z-score > 0), potentially tied to metabolic or immune pathways. Ph-MR analysis pointed to confounding and renal function concerns. ITGA2 was also tied to side effects, including primary biliary cholangitis (OR = 1.35, FDR = 0.0168). Conclusions ITGA2 and ECM1 are causally associated with OSA risk. ITGA2, with a stronger causal effect (MR P = 1.85 × 10⁻⁷, PP.H4 = 0.778), holds greater therapeutic promise. ECM1 displayed stronger colocalization (PP.H4 = 0.902) but a weaker effect and heterogeneity (p_HEIDI = 0.0407), alongside renal function risks, implying an indirect role. This study clarifies OSA’s genetic basis, supporting precision therapy development. ITGA2’s fibrotic role and ECM1’s function and safety warrant further investigation.