Integrative multi-omics quantitative trait loci prioritize CASP7 as a candidate protective gene for cataract

Cataracts are the leading cause of vision loss worldwide. Despite surgery being the only effective treatment, its economic burden highlights the necessity of exploring the pathogenesis of cataracts. In this study, we analyzed 4 large-scale GWAS (genome-wide association study) datasets for cataracts and performed SMR analysis along with heterogeneity in dependent instruments (HEIDI) testing to explore the effects of methylation, expression, and protein QTLs on cataracts. We further validated shared genetic variants through COLOC analysis. Additionally, we searched datasets related to cataracts from the Gene Expression Omnibus (GEO) database for differentially expressed genes (DEGs) and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses. By integrating summary-based Mendelian randomization (SMR) results with bioinformatics findings, CASP7 showed a consistent protective-direction association with cataract risk (mQTL: OR [95% CI] = 0.959 [0.941-0.977], FDR-adjusted P = .039; eQTL: OR [95% CI] = 0.897 [0.860-0.937], FDR-adjusted P = .0046; pQTL: OR [95% CI] = 0.597 [0.483-0.738], FDR-adjusted P = .00083). GEO-based analyses provided transcriptomic support for CASP7 involvement in cataract-related lens biology. These findings prioritize CASP7 as a genetically supported candidate protective gene associated with cataract risk. Because this study is based on public summary-level and transcriptomic datasets, the results should be interpreted cautiously and require functional validation in human lens-relevant systems.