DNA copy number variants of known glaucoma genes in relation to primary open-angle glaucoma.

Liu Y1, Garrett ME2, Yaspan BL3, Bailey JC4, Loomis SJ5, Brilliant M6, Budenz DL7, Christen WG8, Fingert JH9, Gaasterland D10, Gaasterland T11, Kang JH12,Lee RK13, Lichter P14, Moroi SE14, Realini A15, Richards JE14, Schuman JS16, Scott WK17, Singh K18, Sit AJ19, Vollrath D18, Weinreb R20, Wollstein G16, Zack DJ21, Zhang K20, Pericak-Vance MA17, Haines JL4, Pasquale LR22, Wiggs JL5, Allingham RR23, Ashley-Koch AE2, Hauser MA24.

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Abstract

PURPOSE:

We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG).

METHODS:

Our study included DNA samples from two studies (NEIGHBOR and GLAUGEN). All the samples were genotyped with the Illumina Human660W_Quad_v1 BeadChip. After removing non-blood-derived and amplified DNA samples, we applied quality control steps based on the mean Log R Ratio and the mean B allele frequency. Subsequently, data from 3057 DNA samples (1599 cases and 1458 controls) were analyzed with PennCNV software. We defined CNVs as those ≥5 kilobases (kb) in size and interrogated by ≥5 consecutive probes. We further limited our investigation to CNVs in known POAG-related genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, the LRP12-ZFPM2 region, GAS7, ATOH7, FNDC3B, CYP1B1, MYOC, OPTN, WDR36, SRBD1, TBK1, and GALC.

RESULTS:

Genomic duplications of CDKN2B-AS1 and TMCO1 were each found in a single case. Two cases carried duplications in the GAS7 region. Genomic deletions of SIX6 and ATOH7 were each identified in one case. One case carried a TBK1 deletion and another case carried a TBK1 duplication. No controls had duplications or deletions in these six genes. A single control had a duplication in the MYOC region. Deletions of GALC were observed in five cases and two controls.

CONCLUSIONS:

The CNV analysis of a large set of cases and controls revealed the presence of rare CNVs in known POAG susceptibility genes. Our data suggest that these rare CNVs may contribute to POAG pathogenesis and merit functional evaluation.