The path to open-angle glaucoma gene discovery

Endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness

Jac Charlesworth, Patricia L. Kramer, Tom Dyer, Victor Diego, John R. Samples, Jamie E. Craig, David A. Mackey, Alex W. Hewitt, John Blangero, Mary Wirtz

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Purpose. Primary open-angle glaucoma (POAG) is a complex disease with a genetic architecture that can be simplified through the investigation of individual traits underlying disease risk. It has been well studied in twin models, and this study was undertaken to investigate the heritability of some of these key endophenotypes in extended pedigrees. Methods. These data are derived from a large, multicenter study of extended, Caucasian POAG families from Australia and the United States. The study included 1181 people from 22 extended pedigrees. Variance components modeling was used to determine the heritabilities of maximum intraocular pressure (IOP), maximum vertical cup-to-disc ratio (VCDR), and mean central corneal thickness (CCT). Bivariate quantitative genetic analysis between these eye-related phenotypes and POAG itself was performed to determine whether any of these traits represent true endophenotypes. Results. Heritability estimates for IOP, VCDR, and CCT (0.42, 0.66, and 0.72, respectively) were significant and show strong concordance with data in previous studies. Bivariate analysis revealed that both IOP (RhoG = 0.80; P = 9.6 X 10-6) and VCDR (RhoG = 0.76; P = 4.8 X 10-10) showed strong evidence of genetic correlation with POAG susceptibility. These two traits also correlated genetically with each other (RhoG = 0.45; P = 0.0012). Alternatively, CCT did not correlate genetically with risk of POAG. CONCLUSIONS. All the proposed POAG-related traits have genetic components. However, the significant genetic correlations observed between IOP, VCDR, and POAG itself suggest that they most likely represent true endophenotypes that could aid in the identification of genes underlying POAG susceptibility. CCT did not correlate genetically with disease and is unlikely to be a useful surrogate endophenotype for POAG.

Original languageEnglish (US)
Pages (from-to)3509-3514
Number of pages6
JournalInvestigative Ophthalmology and Visual Science
Volume51
Issue number7
DOIs
StatePublished - Jul 2010

Fingerprint

Open Angle Glaucoma
Genetic Association Studies
Intraocular Pressure
Endophenotypes
Pedigree
Primary Open Angle Glaucoma
Twin Studies
Multicenter Studies
Phenotype

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

The path to open-angle glaucoma gene discovery : Endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness. / Charlesworth, Jac; Kramer, Patricia L.; Dyer, Tom; Diego, Victor; Samples, John R.; Craig, Jamie E.; Mackey, David A.; Hewitt, Alex W.; Blangero, John; Wirtz, Mary.

In: Investigative Ophthalmology and Visual Science, Vol. 51, No. 7, 07.2010, p. 3509-3514.

Research output: Contribution to journalArticle

Charlesworth, Jac ; Kramer, Patricia L. ; Dyer, Tom ; Diego, Victor ; Samples, John R. ; Craig, Jamie E. ; Mackey, David A. ; Hewitt, Alex W. ; Blangero, John ; Wirtz, Mary. / The path to open-angle glaucoma gene discovery : Endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness. In: Investigative Ophthalmology and Visual Science. 2010 ; Vol. 51, No. 7. pp. 3509-3514.
@article{36a474ea747440dd8dd8bbc38f663e11,
title = "The path to open-angle glaucoma gene discovery: Endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness",
abstract = "Purpose. Primary open-angle glaucoma (POAG) is a complex disease with a genetic architecture that can be simplified through the investigation of individual traits underlying disease risk. It has been well studied in twin models, and this study was undertaken to investigate the heritability of some of these key endophenotypes in extended pedigrees. Methods. These data are derived from a large, multicenter study of extended, Caucasian POAG families from Australia and the United States. The study included 1181 people from 22 extended pedigrees. Variance components modeling was used to determine the heritabilities of maximum intraocular pressure (IOP), maximum vertical cup-to-disc ratio (VCDR), and mean central corneal thickness (CCT). Bivariate quantitative genetic analysis between these eye-related phenotypes and POAG itself was performed to determine whether any of these traits represent true endophenotypes. Results. Heritability estimates for IOP, VCDR, and CCT (0.42, 0.66, and 0.72, respectively) were significant and show strong concordance with data in previous studies. Bivariate analysis revealed that both IOP (RhoG = 0.80; P = 9.6 X 10-6) and VCDR (RhoG = 0.76; P = 4.8 X 10-10) showed strong evidence of genetic correlation with POAG susceptibility. These two traits also correlated genetically with each other (RhoG = 0.45; P = 0.0012). Alternatively, CCT did not correlate genetically with risk of POAG. CONCLUSIONS. All the proposed POAG-related traits have genetic components. However, the significant genetic correlations observed between IOP, VCDR, and POAG itself suggest that they most likely represent true endophenotypes that could aid in the identification of genes underlying POAG susceptibility. CCT did not correlate genetically with disease and is unlikely to be a useful surrogate endophenotype for POAG.",
author = "Jac Charlesworth and Kramer, {Patricia L.} and Tom Dyer and Victor Diego and Samples, {John R.} and Craig, {Jamie E.} and Mackey, {David A.} and Hewitt, {Alex W.} and John Blangero and Mary Wirtz",
year = "2010",
month = "7",
doi = "10.1167/iovs.09-4786",
language = "English (US)",
volume = "51",
pages = "3509--3514",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "7",

}

TY - JOUR

T1 - The path to open-angle glaucoma gene discovery

T2 - Endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness

AU - Charlesworth, Jac

AU - Kramer, Patricia L.

AU - Dyer, Tom

AU - Diego, Victor

AU - Samples, John R.

AU - Craig, Jamie E.

AU - Mackey, David A.

AU - Hewitt, Alex W.

AU - Blangero, John

AU - Wirtz, Mary

PY - 2010/7

Y1 - 2010/7

N2 - Purpose. Primary open-angle glaucoma (POAG) is a complex disease with a genetic architecture that can be simplified through the investigation of individual traits underlying disease risk. It has been well studied in twin models, and this study was undertaken to investigate the heritability of some of these key endophenotypes in extended pedigrees. Methods. These data are derived from a large, multicenter study of extended, Caucasian POAG families from Australia and the United States. The study included 1181 people from 22 extended pedigrees. Variance components modeling was used to determine the heritabilities of maximum intraocular pressure (IOP), maximum vertical cup-to-disc ratio (VCDR), and mean central corneal thickness (CCT). Bivariate quantitative genetic analysis between these eye-related phenotypes and POAG itself was performed to determine whether any of these traits represent true endophenotypes. Results. Heritability estimates for IOP, VCDR, and CCT (0.42, 0.66, and 0.72, respectively) were significant and show strong concordance with data in previous studies. Bivariate analysis revealed that both IOP (RhoG = 0.80; P = 9.6 X 10-6) and VCDR (RhoG = 0.76; P = 4.8 X 10-10) showed strong evidence of genetic correlation with POAG susceptibility. These two traits also correlated genetically with each other (RhoG = 0.45; P = 0.0012). Alternatively, CCT did not correlate genetically with risk of POAG. CONCLUSIONS. All the proposed POAG-related traits have genetic components. However, the significant genetic correlations observed between IOP, VCDR, and POAG itself suggest that they most likely represent true endophenotypes that could aid in the identification of genes underlying POAG susceptibility. CCT did not correlate genetically with disease and is unlikely to be a useful surrogate endophenotype for POAG.

AB - Purpose. Primary open-angle glaucoma (POAG) is a complex disease with a genetic architecture that can be simplified through the investigation of individual traits underlying disease risk. It has been well studied in twin models, and this study was undertaken to investigate the heritability of some of these key endophenotypes in extended pedigrees. Methods. These data are derived from a large, multicenter study of extended, Caucasian POAG families from Australia and the United States. The study included 1181 people from 22 extended pedigrees. Variance components modeling was used to determine the heritabilities of maximum intraocular pressure (IOP), maximum vertical cup-to-disc ratio (VCDR), and mean central corneal thickness (CCT). Bivariate quantitative genetic analysis between these eye-related phenotypes and POAG itself was performed to determine whether any of these traits represent true endophenotypes. Results. Heritability estimates for IOP, VCDR, and CCT (0.42, 0.66, and 0.72, respectively) were significant and show strong concordance with data in previous studies. Bivariate analysis revealed that both IOP (RhoG = 0.80; P = 9.6 X 10-6) and VCDR (RhoG = 0.76; P = 4.8 X 10-10) showed strong evidence of genetic correlation with POAG susceptibility. These two traits also correlated genetically with each other (RhoG = 0.45; P = 0.0012). Alternatively, CCT did not correlate genetically with risk of POAG. CONCLUSIONS. All the proposed POAG-related traits have genetic components. However, the significant genetic correlations observed between IOP, VCDR, and POAG itself suggest that they most likely represent true endophenotypes that could aid in the identification of genes underlying POAG susceptibility. CCT did not correlate genetically with disease and is unlikely to be a useful surrogate endophenotype for POAG.

UR - http://www.scopus.com/inward/record.url?scp=77955862819&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955862819&partnerID=8YFLogxK

U2 - 10.1167/iovs.09-4786

DO - 10.1167/iovs.09-4786

M3 - Article

VL - 51

SP - 3509

EP - 3514

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 7

ER -