Abstract
Purpose :
Glaucoma is a multifactorial, neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs), optic nerve (ON) damage, and subsequent vision loss. Current treatments focus on lowering intraocular pressure (IOP); however, it is known that some patients continue to experience RGC death despite adequate IOP reduction. Our study aims to identify genes associated with ON health using systems genetics to provide insight for the development of neuroprotective agents.
Methods :
A large cohort of the BXD family were aged to >13 months-of-age. ONs from 75 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of healthy axons per ON cross-section were counted from 1–10 replicates per stain. Phenotype values were averaged per sex, and data were uploaded to GeneNetwork2 for mapping and systems genetics analyses. The trait was mapped using a linear mixed model utilizing the leave-one-chromosome-out method. Genome-wide significance levels (P<0.05) were obtained from 5,000 permutations of the data. Gene-phenotype correlations were performed and considered significant with a Pearson correlation coefficient <0.05.
Results :
The number of healthy axons per ON varies 2.1-fold between the extremes and ranges from 30,000 in BXD98 to 62,000 in BXD20. QTL analysis identified a peak on Chr 9 ranging from 94.66Mb to 105.70 Mb with a logarithm of odds score of 4.27. This region of accounted for 424 positional candidate genes, 213 from the eye database and 211 from the retina database. Five candidates—armadillo repeat containing 8 (Armc8); mitochondrial ribosomal protein L3 (Mrpl3); Eph receptor B1 (Ephb1); Propionyl coenzyme A carboxylase, beta peptide (Pccb); nephronophthisis 3 (Nphp3)—passed stringent criteria and are high priority candidates. These genes were significantly correlated with higher numbers of live axons per ON (R2= 0.38 – 0.46, P= 2.0e-3 – 9.26e-5).
Conclusions :
A genomic region linked to ON health was located on Chr 9 in the BXD family of mice. Using stringent selection criteria, we identified 5 novel gene candidates associated with ON health. Further analysis is necessary to understand each candidate’s role as a plausible therapeutic target and would provide insight for development of future neuroprotective glaucoma treatments.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.