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Eranga N Vithana, Zheng Li, Chiea chuen Khor, Ronnie J George, Chi Pui Pang, Ningli Wang, Kei Tashiro, R. Rand Allingham, Michael A Hauser, Tin Aung; Exome-wide association study identifies a novel locus associated with primary open angle glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2148.
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Primary Open Angle Glaucoma (POAG) is an age-related disease with a significant genetic contribution. To further dissect the genetic architecture of POAG and identify novel genetic variants underpinning POAG susceptibility in Asians, we performed an exome-wide association study.
We used the customized Human Exome Genotyping Bead Chip (Illumina Inc) that contains ~250,000 loci of base content and an additional East Asian specific 25,000 polymorphisms located on the coding frame to genotype 3,822 POAG cases and 10,426 controls from Singapore, China, Hong Kong, Vietnam, Japan, India and USA. All cases were >40 years old and comprised of Normal Tension Glaucoma (NTG) and High Tension Glaucoma (HTG). After quality control filters were applied, 3,506 cases and 9,744 controls remained for statistical analyses. The association between SNP genotypes and POAG risk was measured using unconditional logistic regression, adjusted for the top axes of genetic stratification for the 7 independent collections. SNPs exceeding P < 10-5 for disease association were brought forward for replication in a further 3664 POAG cases and 15,869 controls across 13 collections of Asian, African and Caucasian descent. Meta-analysis summarizing the results across all cohorts was performed using fixed effects modeling weighted in an inverse-variance manner.
We confirmed strong evidence of association at CDKN2BAS (most significant SNP rs2157719; OR =0.73, P = 3.89 x 10-17), previously implicated in POAG. Genome-wide significant association with POAG status was also observed with an intragenic SNP on chromosome 3q26.31 (Overall 20 collections, MAF = 45.6 percent; P = 5.97 x 10-9, per-allele odds ratio = 0.89). Interestingly, this gene displayed a stronger association with POAG in East Asians (East Asian 13 collections; P = 3.26 x 10-10). A novel locus on chromosome 1p22.1 displaying suggestive evidence of association with POAG (MAF = 14.7 percent; P = 1.06 x 10-7, per-allele OR = 1.17) is currently undergoing further validation. Analyses contrasting mutational load of rare, non-synonymous, splice, and non-sense variants with frequencies below 5 percent between POAG cases and controls are currently underway.
We note a potentially novel locus on chromosome 3q26.31 showing strong association with POAG, which could show a stronger predilection in East Asians.
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