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

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 ACSF3, as well as 32 additional SNPs, met genome-wide
significance at P<6.07E-7 or Log10(BF) = 3.0 for GEMMA and
mvBIMBAM, respectively. On chromosome 23, SNPs were located within or near
PCCB and MSL2. On chromosome 30, a SNP was located within IGDCC3. SNPs
associated with coat color were also located within ADAM9, FAM109B,
SULT1C4,RTDR1, BCR, and RGS7. DZIP1L 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 ACSF3 and DZIP1L 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.