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Investigating the genetics of primary open-angle glaucoma in Tasmania


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Charlesworth, Jac Claire 2006 , 'Investigating the genetics of primary open-angle glaucoma in Tasmania', PhD thesis, University of Tasmania.

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Glaucoma is a major cause of visual impairment and the second leading cause of
blindness worldwide. The most common form is adult-onset, primary open-angle
glaucoma (POAG), which has a strong genetic component, with family history an
established risk factor. This dissertation explores several different approaches to the
analysis of extended POAG pedigrees to dissect the genetic aetiology of this
phenotypically and genetically heterogeneous disease. The families were collected as
part of the Glaucoma Inheritance Study in Tasmania (GIST), a study of glaucoma in
Tasmania, representing almost complete population ascertainment of POAG patients.
One aim of this study was to investigate linkage to the POAG loci known at the time in
a selection of 10 extended pedigrees from the GIST. These pedigrees were genotyped
at POAG loci GLC1A, GLC1B, GLC1C, GLC1D, GLC1E and GLC1F, at an average
marker spacing of 4 cM within each locus. Initial Markov chain Monte Carlo based
linkage analyses revealed several suggestive results, and two families were
subsequently selected for fine-mapping and follow-up analyses. One of these, family
GTas15, produced p-values of 0.01 or less at five markers flanked by D251897 and
D2S2269 in the follow-up nonparametric linkage analysis, with a minimum p-value of
0.005 at D2S1897. A 9 cM haplotype of interest was identified, overlapping the
original GLC1B locus. These findings provided supportive evidence for the GLCIB
locus on chromosome 2cen-q13, and verified the existence of a POAG susceptibility
gene in this region.
This study also aimed to identify genetic contributions to POAG by investigating
quantitative components of the disease phenotype. Genome-wide multipoint variancecomponents
linkage analyses of maximum recorded intraocular pressure (lOP) and maximum vertical cup-to-disc ratio were conducted on data from a single, extended
POAG pedigree from the GIST, previously found to segregate the myocilin Q368X
mutation in some individuals. Multipoint linkage analysis of maximum recorded LOP
produced a significant peak LOD score of 3.3 (p=0.00015) near marker D10S537 on
chromosome 10q22, whereas maximum cup-to-disc ratio produced a suggestive peak
LOD score of 2.3 (p=0.00056) near markers DIS197 to DlS220 on chromosome 1p32.
Inclusion of the myocilin Q368X mutation as a covariate provided evidence of an
interaction between this mutation and the LOP and cup-to-disc ratio loci. Identification
of genes contributing to the variance of the quantitative phenotype components of this
disease will enhance understanding of the pathophysiology of POAG as a whole.

Item Type: Thesis - PhD
Authors/Creators:Charlesworth, Jac Claire
Keywords: Open-angle glaucoma, Glaucoma, Eye
Copyright Holders: The Author
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Copyright 2006 the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
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Available for library use only and copying in accordance with the Copyright Act 1968, as amended. Thesis (PhD)--University of Tasmania, 2006. Includes bibliographical references. Ch. 1. Introduction -- Ch. 2. Extended pedigrees from the Glaucoma Inheritance Study in Tasmania -- Ch. 3. Molecular methodology -- Ch. 4. Investigating the known POAG loci GLC1A-F in 10 extended pedigrees from the Glaucoma Inheritance Study in Tasmania -- Ch. 5. Follow-up analysis and fine-mapping of the GLC1B locus in family GTas15 and the GLC1E locus in family GTas35 -- Ch. Variance components analysis of POAG phenotype components using genome-wide scan data from an extended pedigree -- Ch. 7. Discussion -- Conclusions

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