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Mol Genet Genomic Med. 2016 Oct 3;4(6):624-633. eCollection 2016 Nov.

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

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Department of Ophthalmology Flinders University Adelaide SA Australia.
Discipline of OphthalmologyUniversity of SydneySydneyNSWAustralia; Glaucoma UnitSydney Eye HospitalSydneyNSWAustralia.
Discipline of Ophthalmology University of Sydney Sydney NSW Australia.
Menzies Institute for Medical Research University of Tasmania Hobart TAS Australia.
Centre for Ophthalmology and Visual Science Lions Eye Institute University of Western Australia Perth WA Australia.
Discipline of Ophthalmology & Visual Sciences University of Adelaide Adelaide SA Australia.
Diamantina Institute Translational Research Institute Princess Alexandra Hospital University of Queensland Woolloongabba QLD Australia.
Statistical Genetics QIMR Berghofer Medical Research Institute Royal Brisbane Hospital Brisbane QLD Australia.
Department of OphthalmologyFlinders UniversityAdelaideSAAustralia; Menzies Institute for Medical ResearchUniversity of TasmaniaHobartTASAustralia.



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.


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.


Eighty-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).


We 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.


CARD10; genome‐wide association study; rare variants; whole exome sequencing

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