A genome-wide association study to investigate genetic loci associated with primary glaucoma in American Cocker Spaniels

Abstract

OBJECTIVE To identify genetic associations with primary glaucoma (PG) in American Cocker Spaniels using a genome-wide association study (GWAS). ANIMALS A nationwide ambidirectional case–control cohort study was performed in American Cocker Spaniels that had an ophthalmic examination performed by a veterinarian. Ninety-four dogs with PG (cases) and 111 dogs without glaucoma (controls) met phenotypic criteria and had a blood sample collected after receiving informed owner consent. PROCEDURES Genomic DNA was extracted from whole blood samples and genotyped (CanineHD BeadChip, Illumina Inc). A case–control GWAS using a linear mixed model was performed, and 3 significance thresholds were calculated (1) using a Bonferroni correction on all single nucleotide polymorphisms (SNPs) included in the GWAS, (2) using a Bonferroni correction on only the unlinked SNPs from a pruned data set, and (3) using 10,000 random phenotype permutations. RESULTS Following genotype data quality control, 89 cases and 93 controls were included in the GWAS. We identified an association on canine chromosome (CFA10); however, it did not reach statistical significance. Potential candidate genes within the surrounding linkage disequilibrium interval include coiled-coil domain containing 85A (CCDC85A) and extracellular growth factor containing fibulin extracellular matrix protein 1 (EFEMP1). CLINICAL RELEVANCE Primary glaucoma in the American Cocker Spaniel is a complex heterogeneous disease that may be influenced by a locus on CFA10. The candidate genes CCDC85A and EFEMP1 within the identified linkage disequilibrium interval have been shown to be involved in human open-angle glaucoma.

Ocular morphologic traits in the American Cocker Spaniel may confer primary angle closure glaucoma susceptibility

“…This result in combination with the high incidence of PACG in ACS reiterates that canine PACG could be a multifactorial disease having complex genetic traits [5][6][7] . While this study included a modest number of samples for a GWAS, the samples were thoroughly phenotyped and the results are consistent with a previous study with a greater number of samples (> 100 samples for cases and controls, respectively) in this breed where no significant association was identified 12 . Given that canine PACG has a female predilection and is considered an adult-onset disease that does not typically develop until 4-10 years of age 7 , matching controls further based on sex and selecting non-affected controls much older than affected cases may be helpful 14 .…”

“…1 ). Given that a previous study identified a near-significant association at the CFA10 locus in a case–control GWAS within the ACS breed 12 , we further investigated the genotypes at the CFA10 SNP in the present ACS population—85.7% of affected dogs were homozygous for the A allele compared to 62.5% of controls (Supplementary Table S1 ).

Figure 1 Manhattan plot for GWAS (Cases: 28 PACG-affected; Controls: 24 non-affected) in the ACS.

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Ocular Morphologic Traits in the American Cocker Spaniel May Confer Primary Angle Closure Glaucoma Susceptibility

“…1). Given that a previous study identified a near-significant association at the CFA10 locus in a case-control GWAS within the ACS breed 12 , we further investigated the genotypes at the CFA10 SNP in the present ACS population-85.7% of affected dogs were homozygous for the A allele compared to 62.5% of controls (Supplementary Table S1).…”

Genome-Wide Association Studies of Biluochun Tea Plant Populations in Dongting Mountain and Comprehensive Identification of Candidate Genes Associated with Core Agronomic Traits by Four Analysis Models

“…The first three principal components (PCs) and kinship matrix were used as covariates to correct the population structure for decreasing false-positive rate in MLM. Bonferroni correction threshold (p-value = 0.01/marker number or 0.05/marker number) was used to identify significant associations [70]. The p-value of SNPs less than the Bonferroni correction threshold was selected as significant SNPs.…”