Format

Send to

Choose Destination
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.

Author information

1
Department of Ophthalmology Flinders University Adelaide SA Australia.
2
Discipline of OphthalmologyUniversity of SydneySydneyNSWAustralia; Glaucoma UnitSydney Eye HospitalSydneyNSWAustralia.
3
Discipline of Ophthalmology University of Sydney Sydney NSW Australia.
4
Menzies Institute for Medical Research University of Tasmania Hobart TAS Australia.
5
Centre for Ophthalmology and Visual Science Lions Eye Institute University of Western Australia Perth WA Australia.
6
Discipline of Ophthalmology & Visual Sciences University of Adelaide Adelaide SA Australia.
7
Diamantina Institute Translational Research Institute Princess Alexandra Hospital University of Queensland Woolloongabba QLD Australia.
8
Statistical Genetics QIMR Berghofer Medical Research Institute Royal Brisbane Hospital Brisbane QLD Australia.
9
Department of OphthalmologyFlinders UniversityAdelaideSAAustralia; Menzies Institute for Medical ResearchUniversity of TasmaniaHobartTASAustralia.

Abstract

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. 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).

CONCLUSION:

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.

KEYWORDS:

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

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center