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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. |
