April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
The Path to Open Angle Glaucoma Gene Discovery: Using the Endophenotypes, Intraocular Pressure, Central Corneal Thickness and Cup-To-Disc Ratio to Identify POAG-Related Loci
Author Affiliations & Notes
  • J. R. Samples
    Specialty Eye Care, Denver, Colorado
  • J. Charlesworth
    Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
  • P. Kramer
    Neurology and Molecular & Medical Genetics, Oregon Health and Sciences Univesity, Portland, Oregon
  • A. Hewitt
    Ophthalmology, Flinders University, Adelaide, Australia
  • J. E. Craig
    Ophthalmology, Flinders University, Adelaide, Australia
  • T. Dyer
    Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
  • D. Mackey
    Ophthalmology, University of Western Australia, Perth, Australia
  • J. Blangero
    Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
  • Footnotes
    Commercial Relationships  J.R. Samples, None; J. Charlesworth, None; P. Kramer, None; A. Hewitt, None; J.E. Craig, None; T. Dyer, None; D. Mackey, None; J. Blangero, None.
  • Footnotes
    Support  NIH Grants EY10555 (MKW); EY11650 (MKW), EY010572 (MKW), MH059490 (JB); unrestricted grant from RPB to Casey Eye Institute, Supercomputing funding from the ATT Foundation
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 2176. doi:
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      J. R. Samples, J. Charlesworth, P. Kramer, A. Hewitt, J. E. Craig, T. Dyer, D. Mackey, J. Blangero; The Path to Open Angle Glaucoma Gene Discovery: Using the Endophenotypes, Intraocular Pressure, Central Corneal Thickness and Cup-To-Disc Ratio to Identify POAG-Related Loci. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2176.

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Abstract

Purpose: : The purpose of this study was to identify genetic contributions to primary open-angle glaucoma (POAG) through investigations of three quantitative components of the POAG phenotype, intraocular pressure (IOP), vertical cup-to-disc ratio (VCDR) and central corneal thickness (CCT).

Methods: : Genome-wide multipoint variance components linkage analysis of maximum recorded IOP, CDR and CCT were conducted using data from a large multi-center study of extended, Caucasian POAG families from Australia and North America, including 1181 people from 22 extended pedigrees. Variance components analysis was conducted using SOLAR. A population ascertainment correction was used to correct for sampling bias and an empirical LOD adjustment applied to correct for any non-normal trait distributions. This study was conducted in accordance with tenets of the Declaration of Helsinki. Informed consent was obtained from all participants.

Results: : All three traits showed evidence of significant heritability. Multipoint linkage analysis of maximum recorded IOP produced a peak LOD score of 3.87 near marker D3S3672. Analysis of maximum recorded VCDR gave a peak LOD score of 4.02 between D3S1558 and D3S1569, which is coincident with the GLC1C locus on chromosome 3q. Multipoint analysis of minimum recorded CCT produced a peak LOD score of 3.97 near marker D15S118. Age, sex and their interactions as well as population of origin were included as covariates in all analyses.

Conclusions: : Identification of glaucoma susceptibility genes has been hampered by the complexity of the disease, as well as the late age of onset. Using a different approach than the classical Mendelian analysis, we successfully mapped loci for three POAG endophenotypes with LOD scores ≥ 3.0, Thus, utilization of quantitative traits for identification of POAG susceptibility genes combined with the power of family based linkage analysis appears to be a viable option that has the potential for breaking through the barriers to finding new POAG genes.

Keywords: genetics • gene mapping • gene screening 
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