Principal Investigator: Jacquelyn Evans

DESCRIPTION (provided by applicant): 

Chronic superficial keratitis (CSK), also known as pannus, is an immune-related eye disease characterized by vascularized lesions in the cornea that progress to cause blindness if not properly treated. CSK affects many breeds but has especially high incidences in the German shepherd and Belgian shepherd dog breeds. Diagnosis is typically made well after dogs reach breeding age, making the disease difficult to eliminate. Previous studies have associated major histocompatibility complex (MHC) class II haplotypes and upstream regulatory variants with disease in German shepherd dogs in a limited cohort, but further investigation and genome-wide studies are needed. The aims of this project are to (1) identify genomic regions associated with risk for developing CSK in these breeds and (2) investigate and refine associations with the MHC class II dog leukocyte antigen (DLA) genes. For aim 1, we will undertake low-pass whole genome sequencing (2X coverage) followed by imputation and genome-wide association analysis in the German and Belgian shepherd dog breeds. To create a reference panel for accurate imputation of genotypes from low coverage genomes, we will select 10 cases for high coverage (20X) sequencing and include these data with publicly available canine genomes from over 1000 dogs, including representatives of the breeds investigated herein. This approach will provide dense marker data for GWAS, increasing our ability to identify risk loci compared to SNP arrays, and has the potential to reveal causal mutations. Top variants from the GWAS will be investigated for predicted functional impact and association with CSK in a broader cohort. In aim 2, we will directly sequence polymorphic regions of DLA-DRB1, -DQA1, -DQB1 and the variable upstream regulatory regions to independently validate association in our German shepherd dog cohort and to determine whether the same or any three-locus haplotypes confer risk for CSK in the Belgian shepherd dog. The results of this study will be a comprehensive genome-wide investigation of genetic risk for CSK in multiple commonly affected dog breeds that will result in candidate causal variants and ultimately a genetic test that can be used to produce dogs at low risk of developing CSK.