Mitochondria-Related Gene BDH1 Implicated in Myopia Risk via Methylation-Regulated Expression: An Integrative...

The purpose of this study was to prioritize mitochondria-related causal genes (MRGs) involved in myopia by integrating MRGs-related methylation quantitative trait loci (mQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data with myopia genome-wide association study (GWAS) data.

UK Biobank data were utilized for discovery, and FinnGen data for validation. Summary Data-based Mendelian Randomization (SMR) assessed associations between blood-derived MRG-related QTLs and myopia risk, followed by colocalization analysis to evaluate shared genetic etiology. Multi-omics integration linked methylation, expression, and disease risk.

Our integrative SMR analysis of MRGs prioritized BDH1 as the sole robust candidate. We identified a significant association between increased methylation at a promoter-proximal site (cg02569554) and reduced BDH1 expression (odds ratio [OR] = 0.522, 95% confidence interval [CI] = 0.425-0.641, false discovery rate [FDR] = 8.79 × 10⁻⁹). Although other nominal associations were observed, they did not survive multiple testing correction and are thus considered exploratory.

This study provides integrative genetic evidence that BDH1 may contribute to myopia through methylation-regulated expression. However, the findings remain preliminary due to limited cross-layer consistency and require replication and functional validation.

This study prioritizes BDH1 as a mitochondria-related gene that may influence myopia risk via methylation and expression changes, providing a candidate target for mechanistic research and therapeutic intervention.