The underlying hypothesis of this proposal is that identifiable genetic influences play a critical role in the pathophysiology of primary open angle glaucoma (POAG). Furthermore, we believe that the best approach toward identification of the underlying genes is a coordinated attack on this complex disorder utilizing multiple genetic and genomic avenues of investigation, a process that has come to be known as genomic convergence. The major objective of this proposal is to identify the gene that contributes to the development of an early adult onset form of POAG on chromosome 15 (mean family age at diagnosis =45.3 years). We have identified a new genetic locus for POAG on chromosome 15q11-13 through the use of statistical genetic methods suited to the investigation of complex inherited disorders and utilizing a large strictly ascertained database of multiplex POAG families. Using, a novel approach for phenotypic subsetting (ordered subset analysis [OSA]) we have shown that the phenotypic subset of families with an early adult onset form of POAG in the 4th and 5th decades of life (approximately 20% of families within the complete dataset) accounts for the majority of the chromosome 15 linkage information. Our preliminary data suggest that this new locus is a common Mendelian form of POAG. The critical element of this proposal is to apply genomic convergence, or the application of multiple scientific lines of genomic investigation, to determine the genetic contribution of disease. The primary goals of this proposal are threefold: 1) to reduce the minimal candidate interval (MCI) by expanding the size of our early-onset POAG multiplex family dataset and by establishing an association data set of early onset POAG families in conjunction with state of the art molecular and genetic analysis of these data. 2) to create a focused and enriched pool of candidate genes through the use of microarray techniques on human POAG tissue specimens while incorporating the use of existing SAGE/EST libraries;and 3) to analyze candidate genes by sequencing coding regions and conducting association analysis using SNP's. In this manner, we will integrate our family resources, statistical, and molecular expertise to identify the primary genes in POAG. This proposal offers a powerful approach to determine the genetic identity of a major cause of POAG. Determining the molecular underpinnings of POAG will provide enormous benefits in the search for new diagnostic and treatment approaches to this disease.
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