Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation
Description
Abstract
Primary open-angle glaucoma (POAG) is a complex eye disease characterized by progressive loss of optic nerve function that, if untreated, ultimately leads to irreversible blindness. There is disparity in POAG prevalence and manifestations across ancestries, and to date, the biological mechanisms causing POAG are still unclear. Here, we aimed to identify unique genetics that underlie risk to POAG.
We performed POAG meta-analysis across 15 biobanks that are part of the Global Biobank Meta-analysis Initiative, with two previously published multi-ancestry analyses for a total of 1,478,037 individuals from six ancestries (46,325 cases and 1,431,712 controls). A total of 109 genome-wide significantly associated loci were identified, 18 of which were novel. Three of these novel loci are ancestry-specific, two African-specific and the third specific to northern Europeans. We also identified five sex-specific novel loci, four of which are African-specific and one European-specific.
To explore biological implications underlying these variant-trait associations, we performed gene enrichment analysis, gene prioritization analysis and transcriptome-wide association studies (TWAS) implicating genes related to vascular-related functions, blood vessels, angiogenesis, and cancer. A fifth of TWAS-prioritized genes with vascular-related and/or cell senescence/proliferation functional roles or have been implicated in vascular or neoplastic diseases are primary ciliary related genes. Phenome-wide association analysis of POAG genetic risk burden across five biobanks also show the shared biology between POAG and vascular and neoplastic traits.
In summary, our findings suggest that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our findings further support the contribution of vascular and proliferation genes in POAG and suggest potential involvement of primary cilia in POAG pathogenesis.
Explore GBMI GWAS results - interactive Manhattan plot
Explore GBMI meta-analysis results - interactive Manhattan plot