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.
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