Mapping RGC susceptibility alleles

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DESCRIPTION: Glaucoma can be considered a complex genetic disease. One of the striking features of glaucoma is the variable susceptibility to elevated intraocular pressure (IOP) that is present in the general population. Some individuals become ocular hypertensive without ever developing an optic neuropathy, while others develop severe disease with normal or low lOPs. When considering the genetic components of glaucoma, it is likely that allelic variation can affect both the ability of retinal ganglion cells to respond to an apoptotic stimulus and their efficiency of executing the cell death program. To test this possibility, we screened 15 lines of inbred mice to determine if their genetic background affected the loss of retinal ganglion cells after a standardized optic nerve crush procedure. This screen led to the identification of a resistant strain (DBA/2J) and susceptible strain (BALB/cByJ). F1 progeny of an intercross of these strains acquire the resistant phenotype. Analysis of the means and variance of the parental and F1 populations using the Wright formula suggests that DBA/2J animals contribute a dominant allele for resistance to the crush stimulus. We propose to conduct an analysis of this quantitative trait locus. We will generate a mapping population from F2 mice and perform linkage analysis using a selective genotyping approach with informative polymorphic markers that span the genome at -20 cM intervals. Simple linkage will be determined by calculating LOD scores using interval mapping and select regions of significance will be subject to fine mapping. The relevance of this study is that it will provide important information on the genetic mechanisms involved in the process of ganglion cell death in response to an apoptotic stimulus and may identify a critical allele/gene that affects susceptibility to IOP in humans.