Genome-Wide Association Study of ACL Rupture in the Canine Model

Tuesday, September 20, 2016 -
4:00pm to 5:00pm
Room 1360 Biotechnology Center, 425 Henry Mall

Speaker Name: 

Lauren Baker, DVM

Speaker Institution: 

UW School of Veterinary Medicine




Anterior cruciate ligament (ACL) rupture is a common condition that can be devastating and life changing, particularly in young adults. A non-contact mechanism explains most ACL ruptures. Development of a second rupture through rupture of the contralateral ACL or rupture of a graft repair is also common. ACL rupture is also common in dogs. Disease prevalence exceeds 5% in several breeds, ~100-fold higher than humans. We provide insight into the genetic etiology of the ACL rupture condition by performing a genome-wide association study (GWAS) in dogs using three linear mixed models. In the dog, GWAS of 98 cases and 139 controls from the Labrador Retriever breed identified 129 single nucleotide polymorphisms (SNPs) that reside in 98 risk loci. Associated regions (P<5.0E-04) explained approximately half of the phenotypic variance in the ACL rupture trait. Five of these regions were located in uncharacterized or non-coding regions of the genome. A SNP on chromosome 24 that resides in a 5kb haplotype block met genome-wide significance (P=3.63E-06). Genes within this block include BPI, LBP, RALGAPB, ADIG, ARHGAP40, SLC32A1, ACTR5, PPP1R16B, FAM83D, and DHX35. Genotypic risk estimated for each dog based on the risk contributed by each GWAS locus showed clear separation of ACL rupture cases and controls. GWAS pathways were enriched for a cluster of c-type lectins, including aggrecan, antimicrobial pathways, and a gene set encoding membrane transport proteins with a variety of physiological functions. Narrow sense heritability was estimated from pedigree and from SNP markers at 0.49 and 0.47 respectively. In summary, this study provides genetic evidence that ACL rupture is a moderately heritable highly polygenic complex trait. Our results implicate c-type lectin and immunostimulatory signaling pathways in the ACL rupture condition. (This research was done in collaboration with Brian Kirkpatrick2, Guilherme J.M. Rosa, Daniel Ginola, Bruno Valente, Julia Sumner#, Wendy Baltzer, Zhengling Hao, Emily Binversie, Nicola Volstad, Susannah J. Sample, and Peter Muir.)