title: Rare variants in optic disc area geneCARD10enriched in primary open-angle glaucoma.
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.CARD10showed 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.CARD10was 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).
  
  
  CONCLUSIONS
  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 inCARD10may contribute to POAG pathogenesis.
authors.affiliation: Department of Ophthalmology Flinders University Adelaide SA Australia.
authors.forename: Tiger
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Ophthalmology Flinders University Adelaide SA Australia.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Souzeau
authors.affiliation: Department of Ophthalmology Flinders University Adelaide SA Australia.
authors.forename: Shiwani
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Ophthalmology Flinders University Adelaide SA Australia.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Siggs
authors.affiliation: Discipline of OphthalmologyUniversity of SydneySydneyNSWAustralia; Glaucoma UnitSydney Eye HospitalSydneyNSWAustralia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Goldberg
authors.affiliation: Discipline of Ophthalmology University of Sydney Sydney NSW Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Healey
authors.affiliation: Discipline of Ophthalmology University of Sydney Sydney NSW Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Graham
authors.affiliation: Menzies Institute for Medical Research University of Tasmania Hobart TAS Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: Centre for Ophthalmology and Visual Science Lions Eye Institute University of Western Australia Perth WA Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.affiliation: Discipline of Ophthalmology & Visual Sciences University of Adelaide Adelaide SA Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Casson
authors.affiliation: Department of Ophthalmology Flinders University Adelaide SA Australia.
authors.forename: John
authors.initials: J
authors.lastname: Landers
authors.affiliation: Department of Ophthalmology Flinders University Adelaide SA Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Mills
authors.affiliation: Diamantina Institute Translational Research Institute Princess Alexandra Hospital University of Queensland Woolloongabba QLD Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ellis
authors.affiliation: Diamantina Institute Translational Research Institute Princess Alexandra Hospital University of Queensland Woolloongabba QLD Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Leo
authors.affiliation: Diamantina Institute Translational Research Institute Princess Alexandra Hospital University of Queensland Woolloongabba QLD Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Statistical Genetics QIMR Berghofer Medical Research Institute Royal Brisbane Hospital Brisbane QLD Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.affiliation: Department of OphthalmologyFlinders UniversityAdelaideSAAustralia; Menzies Institute for Medical ResearchUniversity of TasmaniaHobartTASAustralia.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: Department of Ophthalmology Flinders University Adelaide SA Australia.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
keywords: CARD10; genome‐wide association study; rare variants; whole exome sequencing