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William Scott, Monique Courtenay, Donald Budenz, Richard Lee, Jonathan Haines, Margaret Pericak-Vance; Exome chip analysis identifies rare variants associated with primary open angle glaucoma. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6246.
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Primary open angle glaucoma (POAG) is a complex disorder with heterogeneous etiology comprising genetic and environmental factors. Family-based linkage studies have identified a few genes with rare mutations underlying POAG, and large case-control studies (and meta-analysis) of common variants have recently reproducibly implicated variants in the CDKN2BAS and SIX1/SIX6 genes. The purpose of this study was to examine rare variants (RV) captured on the human ExomeChip to identify additional POAG genes or RV in existing genes associated with POAG.
White POAG cases (n=314, mean age 73, 75% normotensive POAG) and controls (n=797, mean age 74.5) were genotyped using the Illumina HumanExome-12v1 Array. This array includes coding region variants across the genome, with a majority of variants (88%) being rare (minor allele frequency <5%). POAG cases were evaluated and classified using procedures developed by the NEIGHBOR consortium. After quality control, 243,101 variants were tested for association with POAG using logistic regression models, controlling for population stratification using 5 principal components obtained from EIGENSTRAT.
No variant met Bonferroni criteria (2 x 10-7) for significant association, but 28 coding variants, all in novel genes for POAG, were suggestively associated at p<0.0001. All but one of these variants were more common in controls than cases. The other variant, rs36117280 (M313V), in CACNA1H>, was 1.8 times as likely in cases than controls. Additionally, intronic variants in CDKN2BAS were nominally associated with POAG (p<0.001), as was an intergenic variant in the SIX1/SIX6 region (p<0.05).
Initial analysis of rare coding sequence variants in a POAG sample suggests that such variants may contribute to the complex etiology of POAG. The increase in the CACNA1H (Cav3.2) M313V variant in cases is interesting, given the prior association of POAG with the Cav1/2 region, and further implicates variation in calcium channel genes in POAG.
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