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Genetics  |   December 2014
DNA Copy Number Variants of Known Glaucoma Genes in Relation to Primary Open-Angle Glaucoma
Author Affiliations & Notes
  • Yutao Liu
    Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, United States
    Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States
  • Melanie E. Garrett
    Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States
  • Brian L. Yaspan
    Genentech, Inc., San Francisco, California, United States
  • Jessica Cooke Bailey
    Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States
  • Stephanie J. Loomis
    Department of Ophthalmology, Massachusetts Eye & Ear, Boston, Massachusetts, United States
  • Murray Brilliant
    Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States
  • Donald L. Budenz
    Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States
  • William G. Christen
    Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • John H. Fingert
    Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
  • Douglas Gaasterland
    Eye Doctors of Washington, Chevy Chase, Maryland, United States
  • Terry Gaasterland
    Scripps Genome Center, University of California at San Diego, San Diego, California, United States
  • Jae H. Kang
    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Richard K. Lee
    Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Paul Lichter
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Sayoko E. Moroi
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Anthony Realini
    Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, West Virginia, United States;
  • Julia E. Richards
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Joel S. Schuman
    Department of Ophthalmology, UPMC Eye Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • William K. Scott
    Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Kuldev Singh
    Department of Ophthalmology, Stanford University, Palo Alto, California, United States
  • Arthur J. Sit
    Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
  • Douglas Vollrath
    Department of Ophthalmology, Stanford University, Palo Alto, California, United States
  • Robert Weinreb
    Department of Ophthalmology and Hamilton Glaucoma Center, University of California, San Diego, California, United States
  • Gadi Wollstein
    Department of Ophthalmology, UPMC Eye Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Donald J. Zack
    Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland, United States
  • Kang Zhang
    Department of Ophthalmology and Hamilton Glaucoma Center, University of California, San Diego, California, United States
  • Margaret A. Pericak-Vance
    Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Jonathan L. Haines
    Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States
  • Louis R. Pasquale
    Department of Ophthalmology, Massachusetts Eye & Ear, Boston, Massachusetts, United States
    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Janey L. Wiggs
    Department of Ophthalmology, Massachusetts Eye & Ear, Boston, Massachusetts, United States
  • R. Rand Allingham
    Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States
  • Allison E. Ashley-Koch
    Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States
  • Michael A. Hauser
    Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States
    Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States
  • Correspondence: Yutao Liu, 1460 Laney Walker Boulevard, CB1101, Augusta, GA 30912, USA; yutliu@gru.edu 
Investigative Ophthalmology & Visual Science December 2014, Vol.55, 8251-8258. doi:10.1167/iovs.14-15712
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      Yutao Liu, Melanie E. Garrett, Brian L. Yaspan, Jessica Cooke Bailey, Stephanie J. Loomis, Murray Brilliant, Donald L. Budenz, William G. Christen, John H. Fingert, Douglas Gaasterland, Terry Gaasterland, Jae H. Kang, Richard K. Lee, Paul Lichter, Sayoko E. Moroi, Anthony Realini, Julia E. Richards, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Douglas Vollrath, Robert Weinreb, Gadi Wollstein, Donald J. Zack, Kang Zhang, Margaret A. Pericak-Vance, Jonathan L. Haines, Louis R. Pasquale, Janey L. Wiggs, R. Rand Allingham, Allison E. Ashley-Koch, Michael A. Hauser; DNA Copy Number Variants of Known Glaucoma Genes in Relation to Primary Open-Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(12):8251-8258. doi: 10.1167/iovs.14-15712.

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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.

Introduction
Glaucoma is the second leading cause of irreversible blindness, affecting more than 60 million individuals worldwide, and it is considered to be a heterogeneous group of disorders.14 Primary open-angle glaucoma (POAG) is the most common type and is inherited as a complex trait.2 Clinically, POAG is characterized by progressive retinal ganglion cell death, optic nerve head excavation, and visual field loss.5,6 Risk factors for POAG include increased age, elevated IOP, family history, and African ancestry.2,4,6 Genetic factors have an important role in the pathogenesis of POAG. Family-based linkage studies have identified numerous genomic loci and several genes with varying contribution to POAG, including myocilin (MYOC), cytochrome P450 family 1 subfamily B polypeptide 1 (CYP1B1), optineurin (OPTN), TANK-binding kinase 1 (TBK1), and WD repeat domain 36 (WDR36).2,4,613 Recently, genome-wide association studies (GWAS) of POAG in Iceland, Australia, Japan, and the United States have successfully identified and confirmed a number of genome-wide significant genetic associations in multiple genes, including caveolin 1/caveolin 2 (CAV1/CAV2), CDKN2B antisense RNA 1 (CDKN2B-AS1), transmembrane and coiled-coil domains 1 (TMCO1), SIX homeobox 1/SIX homeobox 6 (SIX1/SIX6), fibronectin type III domain containing 3B (FNDC3B), S1 RNA binding domain 1 (SRBD1), atonal homolog 7 (Drosophila) (ATOH7), and the chr8q22 region between zinc finger protein FOG family member 2 (ZFPM2), and low density lipoprotein receptor-related protein 12 (LRP12).1427 The IOP has been associated with variants in several genes, including TMCO1, ATP-binding cassette subfamily A (ABC1) member 1 (ABCA1) and growth arrest–specific 7 (GAS7).28,29 
In addition, DNA copy number variants (i.e., genomic deletions and duplications) have been shown to have important roles in POAG.3032 Genomic deletions of galactosylceramidase (GALC) and duplications of TBK1 have been reported to contribute to POAG pathogenesis.9,30,31,33,34 A more comprehensive analysis of DNA deletions and duplications of known glaucoma-associated genes is needed to evaluate their possible contribution to the pathogenesis of POAG. To this end, we have studied DNA copy number variants in more than 1599 POAG cases and 1458 eye-examined controls, based on genotype data from the Illumina Human660W_Quad BeadChip (Illumina, San Diego, CA, USA). Here, we report genomic deletions and duplications in a number of known glaucoma-associated genes and their relative contribution to POAG. 
Materials and Methods
Study Population
This study adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all study participants. We used POAG cases and controls from two separate glaucoma cohorts: the Glaucoma Genes and Environment (GLAUGEN) study (dbGaP Study Accession: phs000308.v1.p1, available in the public domain at http://www.ncbi.nlm.nih.gov/gap), which is part of the Gene, Environment Association Study consortium, and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study (dbGAP Study Accession: phs000238.v1.p1, available in the public domain at http://www.ncbi.nlm.nih.gov/gap). Both datasets have been described previously.20,22,3542 Briefly, the GLAUGEN study included 976 cases and 1140 controls from two population-based cohorts: the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), as well as a clinic-based dataset, the Genetic Etiologies of POAG (GEP). The Institutional Review boards of the Massachusetts Eye and Ear Infirmary, Harvard School of Public Health, and Brigham and Women's Hospital approved this study. The NEIGHBOR study consists of 2132 cases and 2290 controls from 12 sites. The institutional review boards of the University of Pittsburgh, Johns Hopkins University, Duke University, University of West Virginia, University of Miami, University of Michigan, Stanford University, Marshfield Clinic, and the University of California, San Diego approved the NEIGHBOR study. 
Eligibility for POAG cases and controls has been described previously.20,35 Briefly, POAG cases had reliable visual field tests showing characteristic visual field defects consistent with glaucomatous optic neuropathy. Elevation of IOP was not a criterion for inclusion. Patients with a diagnosis or history of a secondary glaucoma or ocular trauma were not considered as POAG cases. Trained glaucoma subspecialists reviewed the medical records for all POAG cases and controls to ensure they met inclusion criteria for the study. The examined control individuals were required to have normal optic nerves (cup–disc ratio ≤0.6) and normal IOP (≤21 mm Hg). 
DNA Genotyping and DNA Copy Number Calling
All DNA samples were genotyped using the Illumina Human660W_Quad_v1 BeadChip at the Broad Institute (GLAUGEN), and the Center for Inherited Disease Research (CIDR) (NEIGHBOR).20,35 To minimize batch effects, DNA samples were organized for equal representation of POAG cases and controls per 96-well plate from each study site. The details for DNA collection, extraction and plating, genotype calling, single nucleotide polymorpism (SNP) quality control, and the preliminary analyses in GLAUGEN and NEIGHBOR have been described previously.20,35 After quality control, Illumina's GenomeStudio software was used to generate genotype calls, Log R ratio (LRR), and B allele frequency (BAF) using our established procedure.31 To have a uniform comparison between cases and controls, we removed DNA samples that were whole genome amplified in vitro or were derived from buccal cells or nonblood samples due to their inconsistent copy number variance (CNV) performance compared to blood DNA sample.43 Based on our previous experience in CNV analysis,31 we selected PennCNV software (available in the public domain at www.openbioinformatics.org) to call the CNVs.44,45 PennCNV software combines multiple sources of information, including LRR and BAF at each SNP marker, the distance between neighboring SNPs, and the allele frequency of SNPs. We applied PennCNV to genotyping data generated from Illumina arrays. During the analysis, we further eliminated DNA samples with a SD of the mean LRR > 0.4 or with SD of the mean BAF > 0.1. We also removed DNA samples for which the total number of CNVs was 2 SDs higher than the mean number of CNVs across the entire dataset. After applying these rigorous quality control measures, 1156 POAG cases and 1079 controls from the NEIGHBOR dataset and 443 POAG cases and 379 controls from the GLAUGEN dataset remained for further analysis. To reduce false positives, we also required the CNVs to be at least 5 kilobases (kb) in size and interrogated by a minimum of five consecutive genotyping probes. We restricted our analysis to genomic regions containing glaucoma-associated genes, including MYOC, OPTN, WDR36, CYP1B1, CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, SRBD1, and the intergenic chr8q22 LRP12-ZFPM2 region. 
Results
The demographic characteristics of the NEIGHBOR and GLAUGEN participants included in the study are listed in Table 1. In the NEIGHBOR study, the mean age was 58.0 ± 12.7 years for the cases and 68.0 ± 11.4 for the controls. Similar proportions of female individuals were observed in cases (50.7%) and controls (60.4%). Approximately 40.4% of POAG cases and 8% of controls had a family history of glaucoma in first-degree relatives (i.e., biological parents, siblings, or children). The average number of CNVs (deletions and duplications) in NEIGBHOR was 104 for POAG cases and 103 for the controls. The average size of each CNV was approximately 32 kb for POAG cases and 31 kb for controls. For GLAUGEN samples, the mean age was 65.3 ± 8.3 years for the cases and 64.6 ± 9.5 years for the controls. The proportion of female individuals was similar between cases (56.9%) and controls (52.0%). Of the POAG cases and controls, 52.8% and 12.1%, respectively, had a family history of glaucoma in their first-degree relatives. The average number of CNVs in GLAUGEN was 150 for POAG cases and 163 for the controls. The average size of each CNV in GLAUGEN was approximately 66 kb for POAG cases and 66 kb for the controls. 
Table 1
 
Demographics of POAG Cases and Controls in the NEIGHBOR (1156 Cases and 1079 Controls) and GLAUGEN Datasets (443 Cases and 379 Controls)
Table 1
 
Demographics of POAG Cases and Controls in the NEIGHBOR (1156 Cases and 1079 Controls) and GLAUGEN Datasets (443 Cases and 379 Controls)
NEIGHBOR,n = 2235 GLAUGEN,n = 822
% Female Mean Age ± SD Family History of POAG, % % Female Mean Age ± SD Family History of POAG, %
POAG Case 50.7 58.0 ± 12.7 40.4 56.9 65.3 ± 8.3 52.8
Control 60.4 68.0 ± 11.4 8.0 52.0 64.6 ± 9.5 12.1
We examined the genomic deletions and duplications in known POAG-associated genes, including CAV1/CAV2, CDKN2B-AS1, TMCO1, SIX1/SIX6, FNDC3B, SRBD1, chr8q22 region (LRP12-ZFPM2), GAS7, CYP1B1, OPTN, MYOC, WDR36, TBK1, GALC, and ATOH7 (Table 2). No deletions or duplications were detected in the CAV1/CAV2, CYP1B1, or OPTN genomic regions in our cohorts. As shown in the Figure, we identified one case with a genomic duplication that spans the CDKN2B gene and an intronic region of CDKN2B-AS1 as well as another case with a duplication that spans a majority of the TMCO1 genomic region. Both cases with these duplications were diagnosed in their late 40s with elevated IOPs (>21 mm Hg) and a large vertical cup-to-disc ratio (vCDR) of 0.9 in both eyes. Additionally, in both cases, there was a history of glaucoma in first-degree relatives. A genomic deletion spanning the SIX6 gene and the 5′-end of C14ORF39 gene was identified in one POAG case. This patient had an elevated IOP (>21 mm Hg) and a large vCDR (0.8 in the affected eye) with a positive family history of glaucoma in the first-degree relatives. Two POAG cases with elevated IOPs (>21 mm Hg) carried duplications that span MYH13, MYH8, MYH4, MYH1, and the 5′ end or upstream of the GAS7 gene, which overlaps with the genomic region associated with IOP.28,46 One of these patients had a family history of glaucoma, while the other did not. One POAG case carried a 184 kb TBK1 deletion and another case carried an 886 kb TBK1 duplication, which are CNVs of novel extent. These cases had normal tension glaucoma without a documented history of elevated IOPs (<21 mm Hg). Deletions in the GALC region were found in two controls (one with family history of glaucoma and another without family history) and five POAG cases all of which had elevated IOP (>21 mm Hg) and a positive family history of glaucoma. Deletions of the chr8q22 region (LRP12-ZFPM2) were identified in three cases and two controls (one with and another without family history of glaucoma). Duplications and deletions in the regions of FNDC3B, SRBD1, and WDR36, were equally distributed among POAG cases and controls (Table 2). A deletion in the ATOH7 region was found in one POAG case. This case, with a cup-disc ratio of 0.6 in the left eye and 0.4 in the right eye, had an elevated IOP (>21 mm Hg), reproducible visual field loss, and a positive family history of glaucoma. A duplication in the MYOC region was identified in one control without a family history of glaucoma. 
Figure
 
Representation of rare genetic duplications and deletions in known glaucoma-associated genes in UCSC human genome browser. Green represents genomic duplication and red represents genomic deletion. The boundary of these deletions and duplications is indicated by the edge of these bars.
Figure
 
Representation of rare genetic duplications and deletions in known glaucoma-associated genes in UCSC human genome browser. Green represents genomic duplication and red represents genomic deletion. The boundary of these deletions and duplications is indicated by the edge of these bars.
Table 2
 
Number of Individuals With DNA Copy Number Variants Within Known POAG-Associated Genes in NEIGHBOR (1156 Cases and 1079 Controls) and GLAUGEN (443 Cases and 379 Controls) Datasets
Table 2
 
Number of Individuals With DNA Copy Number Variants Within Known POAG-Associated Genes in NEIGHBOR (1156 Cases and 1079 Controls) and GLAUGEN (443 Cases and 379 Controls) Datasets
NEIGHBOR GLAUGEN Total Combined
Genomic Deletion Genomic Duplication Genomic Deletion Genomic Duplication Deletion Duplication
Case Control Case Control Case Control Case Control Case Control Case Control
CAV1/CAV2 0 0 0 0 0 0 0 0 0 0 0 0
CDKN2B-AS1 0 0 1 0 0 0 0 0 0 0 1 0
TMCO1 0 0 1 0 0 0 0 0 0 0 1 0
SIX1/SIX6 1 0 0 0 0 0 0 0 1 0 0 0
FNDC3B 3 7 0 0 9 7 0 0 12 14 0 0
SRBD1 6 5 0 0 3 3 14 7 9 8 14 7
LRP12-ZFPM2 2 2 0 0 1 0 0 0 3 2 0 0
GAS7 0 0 1 0 0 0 1 0 0 0 2 0
CYP1B1 0 0 0 0 0 0 0 0 0 0 0 0
OPTN 0 0 0 0 0 0 0 0 0 0 0 0
MYOC 0 0 0 0 0 0 0 1 0 0 0 1
WDR36 0 1 5 3 0 1 3 2 0 2 8 5
TBK1 1 0 1 0 0 0 0 0 1 0 1 0
GALC 4 1 0 0 1 1 0 0 5 2 0 0
ATOH7 0 0 0 0 1 0 0 0 1 0 0 0
Discussion
To our knowledge, our study is the largest case-control analysis of CNVs in POAG, including over 3000 participants, and focusing on known POAG-associated genes. We identified a number of rare CNVs in known glaucoma genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, GAS7, TBK1, GALC, and ATOH7. Many CNVs were observed only in POAG patients. However, we also found that the CNVs in three genomic regions (WDR36, FNDC3B, and SRBD1) were relatively common with a frequency greater than 1% in our study. However, the frequencies were not significantly different between POAG cases and controls. The frequencies of these CNVs have not been reported previously to our knowledge. 
Genomic duplications of TBK1 have been specifically associated with POAG in normal tension glaucoma patients.9,33,34 We also identified a genomic duplication of novel extent that spans TBK1 in a POAG case with normal pressure. Our finding provided further support for the genetic contribution of TBK1 duplication in normal tension glaucoma (NTG) pathogenesis. Additionally, for the first time we have identified a genomic deletion of TBK1 in an NTG patient. These results suggested that duplication and deletion of TBK1 contribute to glaucoma. The TBK1 gene encodes a kinase that phosphorylates optineurin, which also is known to cause NTG.10,47,48 Both TBK1 and OPTN participate in autophagy and NF-kB signaling,4,8,49 suggesting that TBK1 CNVs may cause disease by dysregulating these pathways. However, further work is necessary to determine the responsible molecular events. 
Variants in TMCO1 and GAS7 genes recently have been associated with IOP and POAG.28,29,50,51 However, it remains unclear how the protein products from these two genes regulate IOP and affect POAG development. Mutations in TMCO1 have been associated with craniofacial dysmorphism, skeletal anomalies, mental retardation (OMIM *614123) and cerebro-facio-thoracic dysplasia (OMIM #614132).5255 Ocular phenotypes, including IOP elevation or glaucoma, have not been reported previously in patients carrying TMCO1 mutations.5254 However, most of these patients, aged from 3 to 39 years, have macrocephaly, fusion of cervical or thoracic spine, and prominent cerebrospinal fluid (CSF) space,54 which might affect CSF pressure. Decreased CSF pressure has been proposed as a risk factor for glaucoma by increasing the translaminar pressure difference.5658 The GAS7 gene, as part of the growth arrest–specific gene family, is involved in neurite outgrowth and motor neuron function associated with muscle strength maintenance.59,60 The GAS7 regulates the expression of RUNX2 and its dependent transcriptional expression. Mutations in GAS7 increase body fat levels and decrease bone density in mouse models.61 Although variants in the GAS7 genomic region have been associated with IOP level and POAG risk,28,62 the mechanism remains unknown. In addition, ocular phenotypes, including altered IOP, have not been described in the GAS7-deficient mouse.59 The presence of duplications of GAS7 overlapping with IOP-associated regions in two glaucoma patients, but not controls, supports the potential involvement of GAS7 in POAG. However, this does not exclude the possible role of other genes contained within the duplicated region. 
We also identified a rare duplication of CDKN2B/CDKN2B-AS1 in a POAG case. Variants in this genomic region have been associated with POAG, especially with normal-tension glaucoma and advanced glaucoma.16,17,20,50,63 Elevated levels of CDKN2B-AS164 suppress the expression of cell cycle regulators CDKN2A and CDKN2B. Thus, duplication of CDKN2B-AS1 intronic region might increase risk of POAG by elevating gene expression to suppress the expression of CDKN2A and CDKN2B. Of course the actual mechanism remains unknown at this time. Recently, two groups reported that SIX6 is the gene associated with POAG in the SIX1/SIX6 genomic region.38,65 We identified a heterozygous deletion in the SIX6 region. The homozygous loss of SIX6 function in human patients, including homozygous deletion of a large genomic region containing SIX6 gene, has been reported to be associated with variable degrees of retinal hypoplasia, absence of the optic chiasm and optic nerve, and bilateral anophthalmia.6668 However, the individual we have identified with a heterozygous deletion in SIX6 has a much less severe phenotype. It has been proposed that the level of SIX6 expression is associated with POAG although the exact mechanism remains unknown.38,65 Deletions of the GALC genomic region also have been associated with POAG risk.31 In this study we identified more GALC deletions in cases compared to controls. Although the distribution of deletions between cases and controls was not significantly different, it provides further support on the potential contribution of this gene to POAG.4 Variants in ATOH7 have been associated with optic disc size and vertical cup-to-disc ratio14,69,70 as well as POAG.16,25,71 The ATOH7 knockout mouse lacks retinal ganglion cells and optic nerves.72 Deletion of a remote enhancer of ATOH7 disrupts retinal neurogenesis and causes nonsyndromic congenital retinal nonattachment.73 Homozygous ATOH7 mutations were reported in patients with global eye developmental defects, including microphthalmia.74 The POAG case with a heterozygous deletion of ATOH7 represents an intermediate phenotype, suggesting the dosage effect of ATOH7. This is the first report of ATOH7 deletion in a POAG patient. 
We acknowledge that this study had several limitations. First, the detection of CNVs in our samples was based on an Illumina SNP-genotyping array and computational algorithm. Even though this array was designed with the ability to detect CNVs, there are nonetheless limitations to the number of SNP/CNV probes and their ability to detect CNVs. Second, our study focused on genes and loci that have a known or suspected association with POAG and, as such, does not provide information on novel associations, which would have been unlikely due to the uncommon occurrence of CNVs in general. Due to the small number of CNVs in cases and controls, the statistically significant association could not be demonstrated. The frequency of these CNVs in these known glaucoma genes have not yet been reported. This study was designed to lend support to known genes and examine the potential role of gene dosage mechanisms in POAG. Recently, three new studies identified several new genes associated with POAG.26,27,29 However, these results were not available in time to be included in our analysis. Third, these CNVs have not been confirmed by other technologies, such as comparative genomic hybridization array or probe-based real time PCR. Fourth, in this set of unrelated cases and controls, we are not able to demonstrate that interesting CNVs associated with POAG exhibited familial segregation. 
In summary, we reported the analysis of DNA copy number variants of known glaucoma-associated genes in two large POAG case-control sets—NEIGHBOR and GLAUGEN. We identified DNA duplications or deletions in the CDKN2B-AS1, TMCO1, SIX1/SIX6, GAS7, ATOH7, TBK1, and GALC genomic regions in POAG cases. These data suggested that rare CNVs in known glaucoma-associated genes may contribute to POAG pathogenesis potentially through gene dosage effects, and merit further analysis and functional evaluation. 
Acknowledgments
The authors thank all the study participants, without whom this work would not have been possible. The authors thank Hemin Chin, PhD, for institutional support, the Center for Inherited Disease Research, where genotyping services for the NEIGHBOR study were provided, and Cynthia Grosskreutz, Teresa Chen, Doug Rhee, A. Tim Johnson, Judie F. Charlton, Katy Downs, and the Collaborative Initial Glaucoma Treatment Study (CIGTS) investigators and Advanced Glaucoma Intervention Study (AGIS) investigators who helped identify patients and controls for these studies. A full listing of collaborators for GLAUGEN can be found in dbGap at The Primary Open-Angle Glaucoma Genes and Environment (GLAUGEN) Study. Study Accession: phs000308.v1.p1. http://www.ncbi.nlm.nih.gov/projects/gap. December 21, 2010. 
Supported by The Harvard Glaucoma Center of Excellence and Margolis fund (Boston, MA, USA; LRP and JLW); Research to Prevent Blindness, Inc. (New York, NY, USA; LRP, JER and JLW); The Arthur Ashley Foundation (LRP); The Glaucoma Research Foundation (San Francisco, CA, USA), Bright Focus Foundation (formerly called American Health Assistance Foundation, Clarksburg, MD, USA), the Glaucoma Foundation (New York, NY USA), and National Eye Institute Grant R01EY023242 (YL). The NEIGHBORHOOD consortium is supported by National Institutes of Health/National Eye Institute (NIH/NEI; Bethesda, MD, USA) Grant R01EY022305. The maintenance of the Nurses' Health Study and Health Professionals Follow-up was supported by NIH Grants CA87969, CA49449, UM1 CA167552, and HL35464, allowing these health professionals to contribute to this analysis. The following grants from the National Human Genome Research Institute (Bethesda, MD, USA) supported GLAUGEN: HG004728 (LRP), HG004424 (Broad Institute to support genotyping), and HG004446 (Cathy C. Laurie, University of Washington, Seattle, WA, USA, to support genotype data cleaning and analysis). Genotyping services for the NEIGHBOR study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute through Grant HG005259-01 (JLW). In addition, CIDR is funded through a federal contract number HHSN268200782096C from the NIH to The Johns Hopkins University. The NEI, through American Recovery and Reinvestment Act (ARRA) Grants EY015872 (JLW) and EY019126 (MAH), supported the collection and processing of samples for the NEIGHBOR dataset. Funding for the collection of cases and controls was provided by NIH Grants EY015543 (RRA), EY006827 (DG), HL073389 (Elizabeth R. Hauser), P30-EY005722, EY13315 (MAH), EY09611 (Susan E. Hankinson), EY015473 (LRP), EY009149 (PRL), HG004608 (CAM), EY008208 (Felipe A. Medeiros), EY015473 (LRP), EY012118 (MAP-V), EY015682 (TR), EY011671 (JER), EY09580 (JER), EY023512 (JHF), EY013178 (JSS), EY015872 (JLW), EY010886 (JLW), EY009847 (JLW), EY011008 (Linda M. Zangwill), EY144428 (KZ), EY144448 (KZ), and EY18660 (KZ). Supported in part by NIH Grant T32EY021453 (BLY, JNCB). 
Disclosure: Y. Liu, None; M.E. Garrett, None; B.L. Yaspan, None; J.C. Bailey, None; S.J. Loomis, None; M. Brilliant, None; D.L. Budenz, None; W.G. Christen, None; J.H. Fingert, None; D. Gaasterland, None; T. Gaasterland, None; J.H. Kang, None; R.K. Lee, None; P. Lichter, None; S.E. Moroi, None; A. Realini, None; J.E. Richards, None; J.S. Schuman, None; W.K. Scott, None; K. Singh, None; A.J. Sit, None; D. Vollrath, None; R. Weinreb, None; G. Wollstein, None; D.J. Zack, None; K. Zhang, None; M.A. Pericak-Vance, None; J.L. Haines, None; L.R. Pasquale, None; J.L. Wiggs, None; R.R. Allingham, None; A.E. Ashley-Koch, None; M.A. Hauser, None 
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Figure
 
Representation of rare genetic duplications and deletions in known glaucoma-associated genes in UCSC human genome browser. Green represents genomic duplication and red represents genomic deletion. The boundary of these deletions and duplications is indicated by the edge of these bars.
Figure
 
Representation of rare genetic duplications and deletions in known glaucoma-associated genes in UCSC human genome browser. Green represents genomic duplication and red represents genomic deletion. The boundary of these deletions and duplications is indicated by the edge of these bars.
Table 1
 
Demographics of POAG Cases and Controls in the NEIGHBOR (1156 Cases and 1079 Controls) and GLAUGEN Datasets (443 Cases and 379 Controls)
Table 1
 
Demographics of POAG Cases and Controls in the NEIGHBOR (1156 Cases and 1079 Controls) and GLAUGEN Datasets (443 Cases and 379 Controls)
NEIGHBOR,n = 2235 GLAUGEN,n = 822
% Female Mean Age ± SD Family History of POAG, % % Female Mean Age ± SD Family History of POAG, %
POAG Case 50.7 58.0 ± 12.7 40.4 56.9 65.3 ± 8.3 52.8
Control 60.4 68.0 ± 11.4 8.0 52.0 64.6 ± 9.5 12.1
Table 2
 
Number of Individuals With DNA Copy Number Variants Within Known POAG-Associated Genes in NEIGHBOR (1156 Cases and 1079 Controls) and GLAUGEN (443 Cases and 379 Controls) Datasets
Table 2
 
Number of Individuals With DNA Copy Number Variants Within Known POAG-Associated Genes in NEIGHBOR (1156 Cases and 1079 Controls) and GLAUGEN (443 Cases and 379 Controls) Datasets
NEIGHBOR GLAUGEN Total Combined
Genomic Deletion Genomic Duplication Genomic Deletion Genomic Duplication Deletion Duplication
Case Control Case Control Case Control Case Control Case Control Case Control
CAV1/CAV2 0 0 0 0 0 0 0 0 0 0 0 0
CDKN2B-AS1 0 0 1 0 0 0 0 0 0 0 1 0
TMCO1 0 0 1 0 0 0 0 0 0 0 1 0
SIX1/SIX6 1 0 0 0 0 0 0 0 1 0 0 0
FNDC3B 3 7 0 0 9 7 0 0 12 14 0 0
SRBD1 6 5 0 0 3 3 14 7 9 8 14 7
LRP12-ZFPM2 2 2 0 0 1 0 0 0 3 2 0 0
GAS7 0 0 1 0 0 0 1 0 0 0 2 0
CYP1B1 0 0 0 0 0 0 0 0 0 0 0 0
OPTN 0 0 0 0 0 0 0 0 0 0 0 0
MYOC 0 0 0 0 0 0 0 1 0 0 0 1
WDR36 0 1 5 3 0 1 3 2 0 2 8 5
TBK1 1 0 1 0 0 0 0 0 1 0 1 0
GALC 4 1 0 0 1 1 0 0 5 2 0 0
ATOH7 0 0 0 0 1 0 0 0 1 0 0 0
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