Gene ontology and conjunctional false discovery rate statistical framework revealed shared genetic mechanisms underlying glaucoma and myopia

Observational studies have demonstrated that refractive error (RE) is associated with an increased risk of primary open-angle glaucoma (POAG). However, the underlying mechanism through which RE influences the development of POAG remains unknown. In this study, we analyzed genome-wide association study (GWAS) data for RE (95,505 participants) and POAG (15,229 cases and 177,473 controls) to characterize polygenic architecture and identify genetic loci shared of these conditions. We integrated the conjunctional false discovery rate (FDR) statistical framework with Gene ontology to investigate the potential biological mechanisms underlying shared genetic loci. Our study revealed a substantial and previously underexplored shared genetic basis between these disorders. Genetic correlation analysis not only confirms overall genetic correlation between RE and POAG (r for genetic = -0.15, 95%CI: -0.21 to -0.09, P = 7.70E07) but also uncovers localized genetic associations, pointing to 12 genome regions of interest. MR analysis established a bidirectional causal relationship between RE and POAG. We identified a robust polygenic overlap between RE and POAG beyond what conventional genetic correlation analysis can reveal. Moreover, we found substantial polygenic overlap and identified 16 shared loci of RE and POAG at conjFDR < 0.01, of which four were novel. Functional annotation offered insights into potential biological mechanisms through which these genetic loci exert their influence, particularly within retinal tissues. Together, this study significantly advances our understanding of the genetic underpinnings that link RE and POAG, elucidating the complex genetic landscape that contributes to their co-occurrence.