June 2013
Volume 54, Issue 15
ARVO Annual Meeting Abstract  |   June 2013
Exome chip analysis identifies rare variants associated with primary open angle glaucoma
Author Affiliations & Notes
  • William Scott
    Hussman Institute of Human Genomics, University of Miami, Miami, FL
  • Monique Courtenay
    Hussman Institute of Human Genomics, University of Miami, Miami, FL
  • Donald Budenz
    Ophthalmology, University of North Carolina, Chapel Hill, NC
  • Richard Lee
    Bascom Palmer Eye Institute, University of Miami, Miami, FL
  • Jonathan Haines
    Center for Human Genetics Research, Vanderbilt University, Nashville, TN
  • Margaret Pericak-Vance
    Hussman Institute of Human Genomics, University of Miami, Miami, FL
  • Footnotes
    Commercial Relationships William Scott, Duke University/ArcticDx (P); Monique Courtenay, None; Donald Budenz, None; Richard Lee, National Eye Institute (F); Jonathan Haines, Arctic Dx (I), AMD genes (P); Margaret Pericak-Vance, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 6246. doi:
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    • Get Citation

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

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Purpose: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: 539 genetics • 534 gene mapping • 464 clinical (human) or epidemiologic studies: risk factor assessment  

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