April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Exome-wide association study identifies novel loci associated with primary angle closure glaucoma
Author Affiliations & Notes
  • Tin Aung
    Glaucoma, Singapore National Eye Center, Singapore, Singapore
    Ophthalmology, National University of Singapore, Singapore, Singapore
  • Footnotes
    Commercial Relationships Tin Aung, None
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Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2149. doi:
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      Tin Aung, Angle Closure Glaucoma Genetics Consortium; Exome-wide association study identifies novel loci associated with primary angle closure glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2149.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Primary angle closure glaucoma (PACG) is a major form of glaucoma in Asia. We previously reported a genome-wide association study identifying three common genetic variants associated with PACG (Vithana EN et al, Nature Genetics 2012). To further dissect the genetic architecture underling PACG susceptibility, we performed an exome-wide association study.

Methods: We used the exome-wide association approach by deploying the customized Human Exome Genotyping Bead Chip (Illumina Inc) that contains ~250,000 loci of base content as well as an additional 25,000 polymorphisms located on the coding frame which were detected by exome sequencing efforts in East Asians. We collected and genotyped a total of 2,413 PACG cases and 7,870 controls from four independent Asian collections. The association between SNP genotypes and PACG risk was measured using unconditional logistic regression adjusted for the top axes of genetic stratification for each independent collection. SNPs that exceeded P < 10-5 for disease association were brought forward for replication in a further 4,941 PACG cases and 16,612 controls from 10 collections of Asian descent. The most significant genetic associations were further validated in 461 PACG cases and 1,519 controls of European descent. Meta-analysis summarizing the results across all cohorts was performed using fixed effects modeling weighted in an inverse-variance manner.

Results: Genome-wide significant association with PACG status was observed with two non-synonymous amino acid changes at two novel loci, one on chromosome 11p15.1 (338 Gln→Glu, P = 1.30 x 10-10, per-allele odds ratio = 1.14) and another on chromosome 8q11.23 (833 Ser→Asn, P = 2.39 x 10-9, per-allele odds ratio = 0.87). Mutational burden tests performed on uncommon (defined as frequency < 5%) non-synonymous, stop, and potential splice-site mutations revealed suggestive evidence of association at another novel locus.

Conclusions: Our exome-wide association study conducted on >7800 PACG cases and 26,000 controls identified novel loci for PACG. Our findings further increase current understanding on the genes underlying PACG.

Keywords: 539 genetics • 420 anterior chamber  

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