Genetic Etiologies of Primary Open Angle Glaucoma

Summary

Principal Investigator: Janey Wiggs
Abstract: Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. Compelling evidence supports the hypothesis that specific genes influence susceptiblity to the disease. We have previously completed a genome wide screen and follow-up studies that have identified two POAG candidate loci with high likelihood of containing POAG susceptibility genes on chromosomes 14 and 15. The major objective of this proposal is to identify the POAG susceptibility gene(s) located within the defined genetic region on chromosome 14 and determine the relationships between specific genetic defects and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will be the basis of new treatment and diagnostic modalities. To accomplish this overall goal, the size of the minimal genetic interval on chromosome 14 will be reduced by performing linkage analyses on new multiplex families affected with POAG, as well as identifying areas of linkage disequillibrium within the minimal genetic interval using family-based SNP association studies. Known genes and novel gene fragments within the refined minimal genetic interval will be identified using the annotated human genome sequence and will be prioritized for screening using function and expression information from a variety of sources. Identified DNA sequence variants will be examined for biological significance by case/control analyses using a large cohort of POAG cases and age-matched controls. Haplotypes associated with candidate genes will be analyzed using a case/control approach to identify potential regulatory changes that could be missed by sequencing alone. Specific genetic defects will be correlated with clinical phenotype by investigating familial aggregation of clinical parameters and looking for evidence of gene/gene interactions and how these interactions may influence phenotype.
Funding Period: 2005-07-01 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc Association of CAV1/CAV2 genomic variants with primary open-angle glaucoma overall and by gender and pattern of visual field loss
    Stephanie J Loomis
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
    Ophthalmology 121:508-16. 2014
  2. pmc The NEIGHBOR consortium primary open-angle glaucoma genome-wide association study: rationale, study design, and clinical variables
    Janey L Wiggs
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA
    J Glaucoma 22:517-25. 2013
  3. pmc Low prevalence of myocilin mutations in an African American population with primary open-angle glaucoma
    WenJing Liu
    Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA
    Mol Vis 18:2241-6. 2012
  4. pmc The p53 codon 72 PRO/PRO genotype may be associated with initial central visual field defects in caucasians with primary open angle glaucoma
    Janey L Wiggs
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
    PLoS ONE 7:e45613. 2012
  5. pmc CDKN2B-AS1 genotype-glaucoma feature correlations in primary open-angle glaucoma patients from the United States
    Louis R Pasquale
    Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA
    Am J Ophthalmol 155:342-353.e5. 2013
  6. pmc Soluble guanylate cyclase α1-deficient mice: a novel murine model for primary open angle glaucoma
    Emmanuel S Buys
    Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 8:e60156. 2013
  7. pmc Variations in COL15A1 and COL18A1 influence age of onset of primary open angle glaucoma
    J L Wiggs
    Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA, USA
    Clin Genet 84:167-74. 2013
  8. pmc Estrogen pathway polymorphisms in relation to primary open angle glaucoma: an analysis accounting for gender from the United States
    Louis R Pasquale
    Department of Ophthalmology, Mass Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA
    Mol Vis 19:1471-81. 2013
  9. pmc Investigation of known genetic risk factors for primary open angle glaucoma in two populations of African ancestry
    Yutao Liu
    Department of Medicine, Duke University Medical Center, Durham, North Carolina
    Invest Ophthalmol Vis Sci 54:6248-54. 2013
  10. pmc Genome-wide association study and meta-analysis of intraocular pressure
    A Bilge Ozel
    Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
    Hum Genet 133:41-57. 2014

Scientific Experts

  • Janey Wiggs
  • Michael Hauser
  • Marilyn C Cornelis
  • Yutao Liu
  • Louis R Pasquale
  • R Rand Allingham
  • Jae H Kang
  • Julia E Richards
  • Sayoko E Moroi
  • Donald L Budenz
  • Stephanie J Loomis
  • David S Friedman
  • Brian L Yaspan
  • Paul R Lichter
  • Douglas Vollrath
  • Kuldev Singh
  • Donald J Zack
  • Joel S Schuman
  • Kang Zhang
  • Douglas Gaasterland
  • Gadi Wollstein
  • Jonathan L Haines
  • Pratap Challa
  • Leon W Herndon
  • Bao Jian Fan
  • Xuejun Qin
  • Catherine A McCarty
  • Robert N Weinreb
  • Terry Gaasterland
  • Margaret A Pericak-Vance
  • Richard K Lee
  • Tony Realini
  • Megan Ulmer
  • Peter Kraft
  • Silke Schmidt
  • A Bilge Ozel
  • Arthur J Sit
  • Lana Olson
  • MURRAY BRILLIANT
  • William G Christen
  • JOHN FINGERT
  • Allison Ashley-Koch
  • Douglas J Rhee
  • Emmanuel S Buys
  • Jonathan Haines
  • Christopher A Girkin
  • WenJing Liu
  • Jun Li
  • Jason R Gibson
  • Cathy C Laurie
  • John A Heit
  • Nadia N Hansel
  • Mary L Marazita
  • Kristine R Monroe
  • Neil Caporaso
  • Siiri N Bennett
  • Kristy R Crooks
  • T Desronvil
  • Stephen Akafo
  • Jason Gibson
  • Kathleen Scott
  • Hemant Pawar
  • Kari Branham
  • Sarah J Garnai
  • Goncalo Abecasis
  • Melisa Nika
  • Doug Gaasterland
  • Jun Z Li
  • David C Musch
  • Don Zack
  • Louis Pasquale
  • Anand Swaroop
  • John Heckenlively
  • Jesse Gilbert
  • Mohammad Othman
  • Jessica N Cooke Bailey
  • David M Reed
  • Sara Akbari
  • Caroline M Schmidt
  • Wei Chen
  • Frank Rozsa
  • Alexander Jones
  • Shiroh Miura
  • Charles P Lin
  • Allison E Ashley-Koch
  • Douglas E Gaasterland
  • Andrea Giani
  • Lana M Olson
  • Nadine de Waard
  • Jessica Cooke Bailey

Detail Information

Publications22

  1. pmc Association of CAV1/CAV2 genomic variants with primary open-angle glaucoma overall and by gender and pattern of visual field loss
    Stephanie J Loomis
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
    Ophthalmology 121:508-16. 2014
    ..The aim of this study was to assess the association between CAV1/CAV2 single nucleotide polymorphisms (SNPs) and POAG in a large case-control dataset and to explore associations by gender and pattern of visual field (VF) loss further...
  2. pmc The NEIGHBOR consortium primary open-angle glaucoma genome-wide association study: rationale, study design, and clinical variables
    Janey L Wiggs
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA
    J Glaucoma 22:517-25. 2013
    ..In this report we describe the formation of the NEIGHBOR consortium, the harmonized case control definitions used for a POAG GWAS, the clinical features of the cases and controls, and the rationale for the GWAS study design. ..
  3. pmc Low prevalence of myocilin mutations in an African American population with primary open-angle glaucoma
    WenJing Liu
    Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA
    Mol Vis 18:2241-6. 2012
    ..Mutations in the myocilin gene (MYOC) are associated with primary open-angle glaucoma (POAG) in many different populations. This study represents the first large survey of MYOC mutations in an African American population...
  4. pmc The p53 codon 72 PRO/PRO genotype may be associated with initial central visual field defects in caucasians with primary open angle glaucoma
    Janey L Wiggs
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
    PLoS ONE 7:e45613. 2012
    ..In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field...
  5. pmc CDKN2B-AS1 genotype-glaucoma feature correlations in primary open-angle glaucoma patients from the United States
    Louis R Pasquale
    Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA
    Am J Ophthalmol 155:342-353.e5. 2013
    ....
  6. pmc Soluble guanylate cyclase α1-deficient mice: a novel murine model for primary open angle glaucoma
    Emmanuel S Buys
    Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 8:e60156. 2013
    ..These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG...
  7. pmc Variations in COL15A1 and COL18A1 influence age of onset of primary open angle glaucoma
    J L Wiggs
    Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA, USA
    Clin Genet 84:167-74. 2013
    ..These results suggest genetic variation in COL15A1 and COL18A1 can modify the age of onset of both early and late onset POAG. ..
  8. pmc Estrogen pathway polymorphisms in relation to primary open angle glaucoma: an analysis accounting for gender from the United States
    Louis R Pasquale
    Department of Ophthalmology, Mass Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA
    Mol Vis 19:1471-81. 2013
    ..We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender...
  9. pmc Investigation of known genetic risk factors for primary open angle glaucoma in two populations of African ancestry
    Yutao Liu
    Department of Medicine, Duke University Medical Center, Durham, North Carolina
    Invest Ophthalmol Vis Sci 54:6248-54. 2013
    ..Multiple genes have been associated with primary open angle glaucoma (POAG) in Caucasian populations. We now examine the association of these loci in populations of African ancestry, populations at particularly high risk for POAG...
  10. pmc Genome-wide association study and meta-analysis of intraocular pressure
    A Bilge Ozel
    Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
    Hum Genet 133:41-57. 2014
    ..These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk...
  11. pmc Genome-wide analysis of central corneal thickness in primary open-angle glaucoma cases in the NEIGHBOR and GLAUGEN consortia
    Megan Ulmer
    Duke University Center for Human Genetics, Durham, North Carolina 27710, USA
    Invest Ophthalmol Vis Sci 53:4468-74. 2012
    ....
  12. pmc Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma
    Janey L Wiggs
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America
    PLoS Genet 8:e1002654. 2012
    ..009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma...
  13. pmc Detectable clonal mosaicism from birth to old age and its relationship to cancer
    Cathy C Laurie
    Department of Biostatistics, University of Washington, Seattle, Washington, USA
    Nat Genet 44:642-50. 2012
    ....
  14. pmc The Gene, Environment Association Studies consortium (GENEVA): maximizing the knowledge obtained from GWAS by collaboration across studies of multiple conditions
    Marilyn C Cornelis
    Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115
    Genet Epidemiol 34:364-72. 2010
    ..By maximizing knowledge obtained through collaborative GWAS incorporating environmental exposure information, GENEVA aims to enhance our understanding of disease etiology, potentially identifying opportunities for intervention...
  15. pmc Glaucoma: genes, phenotypes, and new directions for therapy
    Bao Jian Fan
    Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA
    J Clin Invest 120:3064-72. 2010
    ..This review summarizes the human genetics and genomic approaches that have shed light on the complex inheritance of glaucoma genes and the potential for gene-based and cellular therapies that this research makes possible...
  16. pmc Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness
    T Desronvil
    Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA
    Mol Vis 16:2185-91. 2010
    ..The purpose of this study is to evaluate COL8A1 and COL8A2 as candidate genes for thin CCT in human POAG patients...
  17. pmc Phenotype harmonization and cross-study collaboration in GWAS consortia: the GENEVA experience
    Siiri N Bennett
    Collaborative Health Studies Coordinating Center, Department of Biostatistics, University of Washington, Seattle, Washington 98115, USA
    Genet Epidemiol 35:159-73. 2011
    ..GENEVA's harmonization efforts and policy of promoting data sharing and collaboration, not only within GENEVA but also with outside collaborations, can provide important guidance to ongoing and new consortia...
  18. pmc Genetic variants associated with optic nerve vertical cup-to-disc ratio are risk factors for primary open angle glaucoma in a US Caucasian population
    Bao Jian Fan
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
    Invest Ophthalmol Vis Sci 52:1788-92. 2011
    ..Recent studies have identified SNPs associated with optic nerve area and vertical cup-to-disc ratio (VCDR). The purpose of this study was to evaluate the association between these SNPs and POAG in a US Caucasian case-control sample...
  19. pmc Genome-wide linkage scan for primary open angle glaucoma: influences of ancestry and age at diagnosis
    Kristy R Crooks
    Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 6:e21967. 2011
    ..These data will prove valuable in the context of interpreting results from genome-wide association studies for POAG...
  20. pmc Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma in Caucasians from the USA
    Janey L Wiggs
    Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA
    Hum Mol Genet 20:4707-13. 2011
    ..We also present data suggesting that associations with several CAV1/CAV2 SNPs are significant mostly in women...
  21. pmc Lack of association between LOXL1 variants and primary open-angle glaucoma in three different populations
    Yutao Liu
    Center for Human Genetics, Duke University Eye Center, Duke University Medical Center, Durham, North Carolina 27710, USA
    Invest Ophthalmol Vis Sci 49:3465-8. 2008
    ..The purpose of this study was to investigate whether XFG-associated variants of LOXL1 play a significant role in primary open-angle glaucoma in the Caucasian, African-American, and Ghanaian (West-African) populations...
  22. ncbi No association between OPA1 polymorphisms and primary open-angle glaucoma in three different populations
    Yutao Liu
    Center for Human Genetics, Duke University Medical Center, Durham, NC, USA
    Mol Vis 13:2137-41. 2007
    ....