The present study was designed to identify genomic loci modulating the susceptibility of retinal ganglion cells (RGC) to elevated intraocular pressure (IOP) in the BXD recombinant inbred mouse strain set. IOP was elevated by injecting magnetic microspheres into the anterior chamber and blocking the trabecular meshwork using a handheld magnet to impede drainage. The IOP was then measured over the next 21 days. Only animals with IOP greater than 25 mmHg for two consecutive days or an IOP above 30 mmHg on a single day after microsphere-injection were used in this study. On day 21, mice were sacrificed and the optic nerve was processed for histology. Axons were counted for both the injected and the control eye in 49 BXD strains, totaling 181 normal counts and 191 counts associated with elevated IOP. The axon loss for each strain was calculated and the data were entered into genenetwork.org. The average number of normal axons in the optic nerve across all strains was 54,788, which dropped to 49,545 in animals with artificially elevated IOP. Interval mapping demonstrated a relatively similar genome-wide map for both conditions with a suggestive Quantitative Trait Locus (QTL) on proximal Chromosome 3. When the relative axon loss was used to generate a genome-wide interval map, we identified one significant QTL (p<0.05) on Chromosome 18 between 56 and 58 Mb. Within this region, the best candidate gene for modulating axon loss was Aldh7a1. In the mouse, we demonstrated the expression of ALDH7A1 in RGCs. When we examined the NEIGHBORHOD database (Glaucoma GWAS), there was no significant association of ALDH7A1 with human primary open-angle glaucoma. We identified a significant QTL on chromosome 18 that modulates axon loss following IOP elevation in the BXD family of mice. Our results suggest that genomic background influences susceptibility to RGC degeneration and death in an inducible glaucoma model.

Genomic Loci Modulating Retinal Ganglion Cell Death Following Elevated IOP in the Mouse