Across-breed genetic investigation of canine hip dysplasia, elbow dysplasia, and anterior cruciate ligament rupture using whole-genome sequencing

Abstract

Here, we report the use of genome-wide association study (GWAS) for the analysis of canine whole-genome sequencing (WGS) repository data using breed phenotypes. Single-nucleotide polymorphisms (SNPs) were called from WGS data from 648 dogs that included 119 breeds from the Dog10K Genomes Project. Next, we assigned breed phenotypes for hip dysplasia (Orthopedic Foundation for Animals (OFA) HD, n = 230 dogs from 27 breeds; hospital HD, n = 279 dogs from 38 breeds), elbow dysplasia (ED, n = 230 dogs from 27 breeds), and anterior cruciate ligament rupture (ACL rupture, n = 279 dogs from 38 breeds), the three most important canine spontaneous complex orthopedic diseases. Substantial morbidity is common with these diseases. Previous within- and between-breed GWAS for HD, ED, and ACL rupture using array SNPs have identified disease-associated loci. Individual disease phenotypes are lacking in repository data. There is a critical knowledge gap regarding the optimal approach to undertake categorical GWAS without individual phenotypes. We considered four GWAS approaches: a classical linear mixed model, a haplotype-based model, a binary case-control model, and a weighted least squares model using SNP average allelic frequency. We found that categorical GWAS was able to validate HD candidate loci. Additionally, we discovered novel candidate loci and genes for all three diseases, including FBX025, IL1A, IL1B, COL27A1, SPRED2 (HD), UGDH, FAF1 (ED), TGIF2 (ED & ACL rupture), and IL22, IL26, CSMD1, LDHA, and TNS1 (ACL rupture). Therefore, categorical GWAS of ancestral dog populations may contribute to the understanding of any disease for which breed epidemiological risk data are available, including diseases for which GWAS has not been performed and candidate loci remain elusive.