Rare variants in optic disc area gene enriched in primary open-angle glaucoma.

Background: Genome-wide association studies (GWAS) have identified association of common alleles with primary open-angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease-associated genes contribute to POAG.

Methods: Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint-called with exomes of 993 previously sequenced Australian controls. GWAS-associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control.

Results: Eighty-six GWAS disease or trait-associated glaucoma genes were captured and sequenced. showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2,  = 6.94 × 10) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12,  = 0.51).

Conclusion: We report here an enrichment of rare predicted pathogenic coding variants within a GWAS-associated locus in POAG (). These findings indicate that both common and rare pathogenic coding variants in may contribute to POAG pathogenesis.