Abstract
Purpose :
Collie eye anomaly (CEA) is an inherited ocular disease with heterogenous clinical signs and progressions. Choroidal hypoplasia is a constant diagnostic feature of CEA with variable presentations of juxtapapillary coloboma (COL). Although genomic regions and genetic variants associated with CEA has been mapped and characterized, the genetic etiology of CEA with COL remains unknown. As such, we performed genome-wide association studies (GWAS) with high-density SNP array and whole-genome sequencing data to identify candidate genomic regions, individual variants and genetic modifiers associated with CEA-COL in dogs.
Methods :
We analyzed 21 canine whole-genome sequences (WGS) including five dogs with 30x and 16 dogs with 15x along with 67 high-density SNP genotyped collies. We performed WGS imputation in SNP-genotyped dogs for combined analyses. After quality control, a total of 5,257,317 SNPs were retained. We used a Bayesian threshold model for whole-genome mapping using population-based case-control studies. We also estimated SNP-based heritability using genomic relationship matrix.
Results :
We estimated a moderate heritability for CEA-COL (h2 = 0.68; 95% CI = 0.23-0.99) suggesting that genetic selection for reducing COL is feasible. Our whole-genome mapping revealed that CEA-COL is a complex trait, and that multiple loci are likely to be important. The association analysis identified at least three different genomic regions on chr15, chr23 and chr8 strongly associated with CEA-COL. The 2.0 Mb SNP window on these three chromosomes explained about 4.40%, 2.05% and 1.91% of the additive genetic variances, respectively. However, upon phasing of these candidate genomic regions, we found a weak trend of segregation of alleles among cases and controls. This could be due to several factors including imperfect segregation of alleles, and presence of other confounding factors. This warrants further studies with larger sample sizes and robust mapping methods.
Conclusions :
Our study demonstrates that GWAS performed with WGS is a powerful complementary method for dissecting genetic basis of CEA-COL. However, further studies with larger sample size will be needed to confirm this finding and identify causal variants.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.