Mouse Genomic Loci Modulating Corneal Thickness

Abstract

Purpose: Central corneal thickness (CCT) is a highly heritable ocular trait that impacts several human disorders including primary open angle glaucoma (POAG).

Methods: We have used a mouse genetic reference panel (the BXD RI strain set) to define mammalian genomic loci modulating CCT with a total of 378 mice from 67 BXD RI strains (between 60-100 days of age). The mice were deeply anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to identify quantitative trait loci (QTLs) modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org).

Results: This analysis reveals one significant QTL on Chr 13 and several suggestive QTLs on Chr 6, Chr 16 and Chr 19. The significant locus on Chr 13 10 to 20 Mb was examined further to define potential candidate genes modulating this eye phenotype. The 13 Mb region under the mouse Chr 13 peak distributes over 4 chromosomes in the human: Chr 1, Chr 6, Chr 7 and Chr 10. Using the eye and retina microarray datasets (HEIMED and HEI Retina) on GeneNetwork, we identified 11 genes with cis-QTLs that could be modulating CCT in the BXD RI strain set. In addition there were 28 genes with nonsynonymous SNPs. Together this represented 38 candidate genes on Chr 13 between 9 and 22 Mb. These candidate genes were examined to determine if they are potential risk factors for human glaucoma using meta-data from the NEIGHBOR-GLAUGEN GWAS. Several SNPs located in an intragenic region near ELMO1 demonstrated nominal significance (p = 0.001 for lead SNP rs9986865).

Conclusions: This approach can identify candidate genes modulating CCT in the mouse and a potential risk factor for primary open angle glaucoma. We are in the process of defining genes in this mouse locus that are associated with the regulation of CCT in humans.