Identification of genetic variants associated with anterior cruciate ligament rupture and AKC standard coat color in the Labrador Retriever

<p>Canine anterior cruciate ligament (ACL) rupture is a common complex disease. Prevalence of ACL rupture is breed-dependent. In an epidemiological study, yellow coat color was associated with increased risk of ACL rupture in the Labrador Retriever. ACL rupture risk variants may be linked to coat color through genetic selection or through linkage with coat color genes. To investigate these associations, Labrador Retrievers were phenotyped as ACL rupture cases or controls and for coat color and were single nucleotide polymorphism (SNP) genotyped. After filtering, ~697K SNPs were analyzed using GEMMA and mvBIMBAM for multivariate association. Functional annotation clustering analysis with DAVID was performed on candidate genes. A large 8Mb region on chromosome 5 that included <em>ACSF3</em>, as well as 32 additional SNPs, met genome-wide significance at <em>P</em>&lt;6.07E-7 or Log₁₀(BF) = 3.0 for GEMMA and mvBIMBAM, respectively. On chromosome 23, SNPs were located within or near <em>PCCB</em> and <em>MSL2</em>. On chromosome 30, a SNP was located within <em>IGDCC3</em>. SNPs associated with coat color were also located within <em>ADAM9</em>,<em> FAM109B</em>,<em> SULT1C4</em>,<em>RTDR1</em>,<em> BCR</em>, and <em>RGS7</em>. <em>DZIP1L</em> was associated with ACL rupture. Several significant SNPs on chromosomes 2, 3, 7, 24, and 26 were located within uncharacterized regions or long non-coding RNA sequences. This study validates associations with the previous ACL rupture candidate genes <em>ACSF3</em> and <em>DZIP1L</em> and identifies novel candidate genes. These variants could act as targets for treatment or as factors in disease prediction modeling. The study highlighted the importance of regulatory SNPs in the disease, as several significant SNPs were located within non-coding regions.</p>