Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

Abstract

AbstractPrimary open-angle glaucoma (POAG) is a leading cause of irreversible blindness globally. There is disparity in POAG prevalence and manifestations across ancestries. We identify novel and unique genetics that underlie POAG risk in different ancestries by performing meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) with previously multi-ancestry studies. 18 novel significant loci, three of which were ancestry-specific, and five sex-specific were identified. We performed gene-enrichment and transcriptome-wide association studies (TWAS), implicating vascular and cancer genes. A fifth of these genes are primary ciliary genes. Extensive statistical analysis of genes in the SIX6 and CDKN2B-AS1 loci (implicated in POAG, cardiovascular diseases and cancers) found interaction between SIX6 and causal variants in chr9p21.3, with expression effect on CDKN2A/B. We infer that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our results further support the contribution of vascular, cancer, and primary cilia genes in POAG pathogenesis.