Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma.

Tiger Zhou,Stuart Graham,Kathryn P Burdon,Stuart Macgregor,Owen M Siggs,Robert J Casson,Paul Leo,Ivan Goldberg,Paul R Healey,Emmanuelle Souzeau,Alex W Hewitt,Matthew A Brown,David A Mackey,John Landers,Jonathan Ellis,Jamie E Craig,Shiwani Sharma,Richard Mills

doi:10.1002/mgg3.248

Abstract

BackgroundGenome‐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.MethodsParticipants 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.ResultsEighty‐six GWAS disease or trait‐associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 × 10−5) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12, P = 0.51).ConclusionWe report here an enrichment of rare predicted pathogenic coding variants within a GWAS‐associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.

Highlights

Glaucoma is the most common cause of irreversible and preventable blindness and the second most common cause of all blindness after cataract, accounting for 8% of blindness worldwide in 2010 (Pascolini and Mariotti 2012)
These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to primary open-angle glaucoma (POAG) pathogenesis
101 genes have been reported by Genome-wide association studies (GWAS) studies as being near single-nucleotide polymorphism (SNP) that are statistically associated with POAG, central corneal thickness, intraocular pressure (IOP) or optic disc morphology

Summary

Introduction

Glaucoma is the most common cause of irreversible and preventable blindness and the second most common cause of all blindness after cataract, accounting for 8% of blindness worldwide in 2010 (Pascolini and Mariotti 2012). With early identification and intervention, mainly with intraocular pressure (IOP)-lowering therapy, vision loss is usually preventable (Leske et al 2003). Primary open-angle glaucoma (POAG) is the most common disease subset and the high IOP phenotype is predominant in Caucasian and African ethnicities (Tham et al 2014). While elevated IOP is the single greatest risk factor for POAG, other associated endophenotypes include optic disc morphology and central corneal thickness (CCT) (Miglior et al 2007; Jiang et al 2012; Hollands et al 2013). 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

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