Yutao Liu1, Melanie E Garrett2, Brian L Yaspan3, Jessica Cooke Bailey4, Stephanie J Loomis5, Murray Brilliant6, Donald L Budenz7, William G Christen8, John H Fingert9, Douglas Gaasterland10, Terry Gaasterland11, Jae H Kang12, Richard K Lee13, Paul Lichter14, Sayoko E Moroi14, Anthony Realini15, Julia E Richards14, Joel S Schuman16, William K Scott17, Kuldev Singh18, Arthur J Sit19, Douglas Vollrath18, Robert Weinreb20, Gadi Wollstein16, Donald J Zack21, Kang Zhang20, Margaret A Pericak-Vance17, Jonathan L Haines4, Louis R Pasquale22, Janey L Wiggs5, R Rand Allingham23, Allison E Ashley-Koch2, Michael A Hauser24. 1. 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. 2. Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States. 3. Genentech, Inc., San Francisco, California, United States. 4. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States. 5. Department of Ophthalmology, Massachusetts Eye & Ear, Boston, Massachusetts, United States. 6. Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States. 7. Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States. 8. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States. 9. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States. 10. Eye Doctors of Washington, Chevy Chase, Maryland, United States. 11. Scripps Genome Center, University of California at San Diego, San Diego, California, United States. 12. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States. 13. Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, United States. 14. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States. 15. Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, West Virginia, United States; 16. Department of Ophthalmology, UPMC Eye Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States. 17. Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States. 18. Department of Ophthalmology, Stanford University, Palo Alto, California, United States. 19. Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States. 20. Department of Ophthalmology and Hamilton Glaucoma Center, University of California, San Diego, California, United States. 21. Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland, United States. 22. Department of Ophthalmology, Massachusetts Eye & Ear, Boston, Massachusetts, United States Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States. 23. Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States. 24. Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.
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. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
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. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
Entities:
Keywords:
DNA copy number variants; GAS7; POAG; SIX6; genetics
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