Systematic genomic Mendelian randomization profiling of early molecular markers of optic atrophy

To identify early molecular diagnostic biomarkers for optic atrophy (OPA) and explore potential mechanisms mediated by proteins.

Gene expression data was sourced from eQTLGen (31684 samples; 19960 genes). The OPA discovery cohort came from FinnGen (629 cases; 496621 controls); the validation cohort came from the genome-wide association studies (GWAS) catalog (58 cases; 496621 controls). Protein data for mediation analysis was obtained from the deCODE Genetics consortium (35559 samples; 4907 proteins). Causal estimates were derived using two-sample Mendelian randomization (MR). Inverse-variance weighted (IVW) was the primary analysis method. Sensitivity analyses included MR-Egger intercept, Cochran’s Q test for heterogeneity, and leave-one-out analysis. Colocalization analysis validated identified genes. Additionally, interaction analysis identified potential biomarkers. Finally, mediation analysis assessed potential mediating mechanisms.

Multi-cohort validation revealed that increased expression levels of the SEC61A2 and THNSL2 were causally associated with an elevated risk of OPA. Furthermore, we identified 386 genes potentially associated with OPA. Hormone secretion and immune-related pathways were found to play significant roles in OPA pathogenesis. Mediation analysis indicated that Upper zone of growth plate and cartilage matrix associated (UCMA) potentially mediates the effect of SEC61A2 in increasing OPA risk.

SEC61A2 and THNSL2 may serve as early diagnostic biomarkers for OPA. Additionally, SEC61A2 likely increases OPA risk through UCMA.