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Monica M Jablonski, Eric Sah, Raven Davis, XiangDi Wang, Lu Lu, Robert W. Williams; Systems Genetics of Optic Nerve Axon Necrosis and IOP. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1626.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is a multifactorial, neurodegenative disease that targets axons of retinal ganglion cells (RGCs). It is the leading cause of irreversible blindness worldwide. The various subtypes of glaucoma share the common clinical pathologies of RGC axonal necrosis and visual field loss. Intraocular pressure (IOP) is the primary risk factor for glaucoma. In primary open angle glaucoma (POAG), both optic nerve (ON) damage and IOP are highly heritable, and the genetic risk of elevated IOP and POAG are partially shared. However, many gene loci associated with POAG are not associated with IOP. In this study we sought to identify genomic region that modulates axon necrosis in the ON and define a high priority set of positional candidate genes that control RGC axon degeneration. We further sought to determine if the gene modulators of RGC axon necrosis and IOP were partially shared.
A large cohort of the BXD family of mice were aged to greater than 13 months. Optic nerves from 75 BXD strains and the DBA/2J (D2) parental strain were harvested, sectioned, and stained with p-phenylenediamine. The number of necrotic axons per ON were counted using ImagePad software. Data were uploaded to GeneNetwork for mapping and systems genetics analyses. Comparison to IOP data previously compiled was also performed.
Using simple interval mapping, we identified a single locus on Chr 12 between 104 and 116 Mb with a likelihood ratio statistic (LRS) of 19. Of 320 positional candidates, six genes—Apopt1, Cdc42bpb, Eif5, Serpina3g, Tmem179, and Xrcc3—remain high priority candidates. Additional studies are in progress to identify the causative variant. Loci that modulate ON necrosis and IOP were found on different chromosomes. Comparison of the top genetic correlates for both traits demonstrated that <5% of the genes were shared.
In this study, we identified a locus on Chr 12 that modulates the degree of ON necrosis in the BXD family and narrowed the list of positional candidates. Our recent identification of an IOP-modulating locus on Chr 5 demonstrates that these two glaucoma-associated traits are independently regulated. Moreover, they function in non-overlapping functional and molecular pathways, which would directly affect the onset of glaucoma, rates of axon death, and responses to therapeutic interventions.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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