A Genome-Wide Association Study for Primary Open Angle Glaucoma and Macular Degeneration Reveals Novel Loci

PLOS ONE, Dec 2019

Glaucoma and age-related macular degeneration (AMD) are the two leading causes of visual loss in the United States. We utilized a novel study design to perform a genome-wide association for both primary open angle glaucoma (POAG) and AMD. This study design utilized a two-stage process for hypothesis generation and validation, in which each disease cohort was utilized as a control for the other. A total of 400 POAG patients and 400 AMD patients were ascertained and genotyped at 500,000 loci. This study identified a novel association of complement component 7 (C7) to POAG. Additionally, an association of central corneal thickness, a known risk factor for POAG, was found to be associated with ribophorin II (RPN2). Linked monogenic loci for POAG and AMD were also evaluated for evidence of association, none of which were found to be significantly associated. However, several yielded putative associations requiring validation. Our data suggest that POAG is more genetically complex than AMD, with no common risk alleles of large effect.

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A Genome-Wide Association Study for Primary Open Angle Glaucoma and Macular Degeneration Reveals Novel Loci

et al. (2013) A Genome-Wide Association Study for Primary Open Angle Glaucoma and Macular Degeneration Reveals Novel Loci. PLoS ONE 8(3): e58657. doi:10.1371/journal.pone.0058657 A Genome-Wide Association Study for Primary Open Angle Glaucoma and Macular Degeneration Reveals Novel Loci Todd E. Scheetz 0 John H. Fingert 0 Kai Wang 0 Markus H. Kuehn 0 Kevin L. Knudtson 0 Wallace L. M. Alward 0 H. Culver Boldt 0 Stephen R. Russell 0 James C. Folk 0 Thomas L. Casavant 0 Terry A. Braun 0 Abbot F. Clark 0 Edwin M. Stone 0 Val C. Sheffield 0 Pedro Gonzalez, Duke University, United States of America 0 1 Department of Ophthalmology and Visual Sciences, The University of Iowa , Iowa City , Iowa, United States of America, 2 Department of Biomedical Engineering, The University of Iowa , Iowa City , Iowa, United States of America, 3 Center for Bioinformatics and Computational Biology, The University of Iowa , Iowa City , Iowa, United States of America, 4 Department of Biostatistics, The University of Iowa , Iowa City , Iowa, United States of America , 5 DNA Core Facility , The University of Iowa , Iowa City , Iowa, United States of America, 6 Department of Electrical and Computer Engineering, The University of Iowa , Iowa City , Iowa, United States of America, 7 Department of Cell Biology and Anatomy, The University of Iowa , Iowa City , Iowa, United States of America, 8 North Texas Eye Research Institute, University of North Texas Health Sciences Center, Fort Worth, Texas, United States of America, 9 Department of Pediatrics, Howard Hughes Medical Institute , Iowa City , Iowa, United States of America, 10 Howard Hughes Medical Institute , Iowa City, Iowa , United States of America Glaucoma and age-related macular degeneration (AMD) are the two leading causes of visual loss in the United States. We utilized a novel study design to perform a genome-wide association for both primary open angle glaucoma (POAG) and AMD. This study design utilized a two-stage process for hypothesis generation and validation, in which each disease cohort was utilized as a control for the other. A total of 400 POAG patients and 400 AMD patients were ascertained and genotyped at 500,000 loci. This study identified a novel association of complement component 7 (C7) to POAG. Additionally, an association of central corneal thickness, a known risk factor for POAG, was found to be associated with ribophorin II (RPN2). Linked monogenic loci for POAG and AMD were also evaluated for evidence of association, none of which were found to be significantly associated. However, several yielded putative associations requiring validation. Our data suggest that POAG is more genetically complex than AMD, with no common risk alleles of large effect. - Funding: This work was supported by the National Institutes of Health [R01-EY-010564 to VCS, R01-EY-016822 to EMS, R01-EY-018825 to JHF]; the Carver Endowment for Molecular Ophthalmology to EMS and VCS; Research to Prevent Blindness (Department of Ophthalmology, University of Iowa, Career Development Awards to TES and JHF, and the Lew Wasserman Award to WLMA); and Foundation Fighting Blindness. VCS and EMS are investigators of the Howard Hughes Medical Institute. Alcon Research, Ltd. (Ft. Worth, Texas) provided funds for the purchase of the SNP genotyping chips used in this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: This research was supported in part by Alcon Research Ltd, specifically in acquisition of the genotyping arrays. This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. Age-related macular degeneration (AMD) and glaucoma are leading causes of blindness and visual disability in aging populations. Although these conditions are unrelated, each has a strong genetic component. The glaucomas are a group of diseases that are characterized by injury to the optic nerve and a corresponding pattern of visual loss. These disorders are the second most common cause of irreversible blindness and visual impairment in the United States.[1] The most common form of glaucoma in the United States is primary open angle glaucoma (POAG). Epidemiological studies have shown that POAG is caused, at least in part, by heritable factors. Classic risk factors for glaucoma include advanced age, ethnicity, elevated intraocular pressure, and family history. More recently individuals with relatively thin corneas have been shown to have a three-fold greater risk of developing glaucoma than individuals with normal corneal thickness[2]. Most cases of POAG, and indeed the risk factors of elevated IOP and thin central corneal thickness, are thought to be inherited in a complex fashion[3,4]. While the genetics of glaucoma are overall complex, a fraction of glaucoma is caused primarily by defects or mutations in single genes. Linkage studies of large families exhibiting autosomal dom (...truncated)


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Todd E. Scheetz, John H. Fingert, Kai Wang, Markus H. Kuehn, Kevin L. Knudtson, Wallace L. M. Alward, H. Culver Boldt, Stephen R. Russell, James C. Folk, Thomas L. Casavant, Terry A. Braun, Abbot F. Clark, Edwin M. Stone, Val C. Sheffield. A Genome-Wide Association Study for Primary Open Angle Glaucoma and Macular Degeneration Reveals Novel Loci, PLOS ONE, 2013, Volume 8, Issue 3, DOI: 10.1371/journal.pone.0058657