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Genome-wide association analysis in dogs implicates 99 loci as risk variants for anterior cruciate ligament rupture.

ABSTRACT: Anterior cruciate ligament (ACL) rupture is a common condition that can be devastating and life changing, particularly in young adults. A non-contact mechanism is typical. Second ACL ruptures through rupture of the contralateral ACL or rupture of a graft repair is also common. Risk of rupture is increased in females. ACL rupture is also common in dogs. Disease prevalence exceeds 5% in several dog breeds, ~100 fold higher than human beings. We provide insight into the genetic etiology of ACL rupture by genome-wide association study (GWAS) in a high-risk breed using 98 case and 139 control Labrador Retrievers. We identified 129 single nucleotide polymorphisms (SNPs) within 99 risk loci. Associated loci (P<5E-04) explained approximately half of phenotypic variance in the ACL rupture trait. Two of these loci were located in uncharacterized or non-coding regions of the genome. A chromosome 24 locus containing nine genes with diverse functions met genome-wide significance (P = 3.63E-0.6). GWAS pathways were enriched for c-type lectins, a gene set that includes aggrecan, a gene set encoding antimicrobial proteins, and a gene set encoding membrane transport proteins with a variety of physiological functions. Genotypic risk estimated for each dog based on the risk contributed by each GWAS locus showed clear separation of ACL rupture cases and controls. Power analysis of the GWAS data set estimated that ~172 loci explain the genetic contribution to ACL rupture in the Labrador Retriever. Heritability was estimated at 0.48. We conclude ACL rupture is a moderately heritable highly polygenic complex trait. Our results implicate c-type lectin pathways in ACL homeostasis.

SUBMITTER: Baker LA

PROVIDER: S-EPMC5381864 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Genome-wide association analysis in dogs implicates 99 loci as risk variants for anterior cruciate ligament rupture.

Baker Lauren A LA Kirkpatrick Brian B Rosa Guilherme J M GJ Gianola Daniel D Valente Bruno B Sumner Julia P JP Baltzer Wendy W Hao Zhengling Z Binversie Emily E EE Volstad Nicola N Piazza Alexander A Sample Susannah J SJ Muir Peter P

PloS one 20170405 4

Anterior cruciate ligament (ACL) rupture is a common condition that can be devastating and life changing, particularly in young adults. A non-contact mechanism is typical. Second ACL ruptures through rupture of the contralateral ACL or rupture of a graft repair is also common. Risk of rupture is increased in females. ACL rupture is also common in dogs. Disease prevalence exceeds 5% in several dog breeds, ~100 fold higher than human beings. We provide insight into the genetic etiology of ACL rupt ...[more]

PMID: 28379989

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Project description:Anterior cruciate ligament (ACL) rupture is an important condition of the human knee. Second ruptures are common and societal costs are substantial. Canine cranial cruciate ligament (CCL) rupture closely models the human disease. CCL rupture is common in the Labrador Retriever (5.79% prevalence), ~100-fold more prevalent than in humans. Labrador Retriever CCL rupture is a polygenic complex disease, based on genome-wide association study (GWAS) of single nucleotide polymorphism (SNP) markers. Dissection of genetic variation in complex traits can be enhanced by studying structural variation, including copy number variants (CNVs). Dogs are an ideal model for CNV research because of reduced genetic variability within breeds and extensive phenotypic diversity across breeds. We studied the genetic etiology of CCL rupture by association analysis of CNV regions (CNVRs) using 110 case and 164 control Labrador Retrievers. CNVs were called from SNPs using three different programs (PennCNV, CNVPartition, and QuantiSNP). After quality control, CNV calls were combined to create CNVRs using ParseCNV and an association analysis was performed. We found no strong effect CNVRs but found 46 small effect (max(T) permutation P<0.05) CCL rupture associated CNVRs in 22 autosomes; 25 were deletions and 21 were duplications. Of the 46 CCL rupture associated CNVRs, we identified 39 unique regions. Thirty four were identified by a single calling algorithm, 3 were identified by two calling algorithms, and 2 were identified by all three algorithms. For 42 of the associated CNVRs, frequency in the population was <10% while 4 occurred at a frequency in the population ranging from 10-25%. Average CNVR length was 198,872bp and CNVRs covered 0.11 to 0.15% of the genome. All CNVRs were associated with case status. CNVRs did not overlap previous canine CCL rupture risk loci identified by GWAS. Associated CNVRs contained 152 annotated genes; 12 CNVRs did not have genes mapped to CanFam3.1. Using pathway analysis, a cluster of 19 homeobox domain transcript regulator genes was associated with CCL rupture (P = 6.6E-13). This gene cluster influences cranial-caudal body pattern formation during embryonic limb development. Clustered genes were found in 3 CNVRs on chromosome 14 (HoxA), 28 (NKX6-2), and 36 (HoxD). When analysis was limited to deletion CNVRs, the association was strengthened (P = 8.7E-16). This study suggests a component of the polygenic risk of CCL rupture in Labrador Retrievers is associated with small effect CNVs and may include aspects of stifle morphology regulated by homeobox domain transcript regulator genes.

Project description:BACKGROUND:Anterior cruciate ligament rupture (ACLR) is a debilitating and potentially life-changing condition in humans, as there is a high prevalence of early-onset osteoarthritis after injury. Identification of high-risk individuals before they become patients is important, as post-treatment lifetime burden of ACLR in the USA ranges from $7.6 to $17.7 billion annually. ACLR is a complex disease with multiple risk factors including genetic predisposition. Naturally occurring ACLR in the dog is an excellent model for human ACLR, as risk factors and disease characteristics in humans and dogs are similar. In a univariate genome-wide association study (GWAS) of 237 Labrador Retrievers, we identified 99 ACLR candidate loci. It is likely that additional variants remain to be identified. Joint analysis of multiple correlated phenotypes is an underutilized technique that increases statistical power, even when only one phenotype is associated with the trait. Proximal tibial morphology has been shown to affect ACLR risk in both humans and dogs. In the present study, tibial plateau angle (TPA) and relative tibial tuberosity width (rTTW) were measured on bilateral radiographs from purebred Labrador Retrievers that were recruited to our initial GWAS. We performed a multivariate genome wide association analysis of ACLR status, TPA, and rTTW. RESULTS:Our analysis identified 3 loci with moderate evidence of association that were not previously associated with ACLR. A locus on Chr1 associated with both ACLR and rTTW is located within ROR2, a gene important for cartilage and bone development. A locus on Chr4 associated with both ACLR and TPA resides within DOCK2, a gene that has been shown to promote immune cell migration and invasion in synovitis, an important predictor of ACLR. A third locus on Chr23 associated with only ACLR is located near a long non-coding RNA (lncRNA). LncRNA's are important for regulation of gene transcription and translation. CONCLUSIONS:These results did not overlap with our previous GWAS, which is reflective of the different methods used, and supports the need for further work. The results of the present study are highly relevant to ACLR pathogenesis, and identify potential drug targets for medical treatment.

Project description:BackgroundAnterior cruciate ligament (ACL) graft rupture occurs at a high rate, especially in young athletes. The geometries of the tibial plateau and femoral intercondylar notch are risk factors for first-time ACL injury; however, little is known about the relationship between these geometries and risk of ACL graft rupture.HypothesisThe geometric risk factors for noncontact graft rupture are similar to those previously identified for first-time noncontact ACL injury, and sex-specific differences exist.Study designCase-control study; Level of evidence, 3.MethodsEleven subjects who suffered a noncontact ACL graft rupture and 44 subjects who underwent ACL reconstruction but did not experience graft rupture were included in the study. Using magnetic resonance imaging, the geometries of the tibial plateau subchondral bone, articular cartilage, meniscus, tibial spines, and femoral notch were measured. Risk factors associated with ACL graft rupture were identified using Cox regression.ResultsThe following were associated with increased risk of ACL graft injury in males: increased posterior-inferior-directed slope of the articular cartilage in the lateral tibial plateau measured at 2 locations (hazard ratio [HR] = 1.50, P = .029; HR = 1.39, P = .006), increased volume (HR = 1.45, P = .01) and anteroposterior length (HR = 1.34, P = .0023) of the medial tibial spine, and increased length (HR = 1.18, P = .0005) and mediolateral width (HR = 2.19, P = .0004) of the lateral tibial spine. In females, the following were associated with increased risk of injury: decreased volume (HR = 0.45, P = .02) and height (HR = 0.46, P = .02) of the medial tibial spine, decreased slope of the lateral tibial subchondral bone (HR = 0.72, P = .01), decreased height of the posterior horn of the medial meniscus (HR = 0.09, P = .001), and decreased intercondylar notch width at the anterior attachment of the ACL (HR = 0.72, P = .02).ConclusionThe geometric risk factors for ACL graft rupture are different for males and females. For females, a decreased femoral intercondylar notch width and a decreased height of the posterior medial meniscus were risk factors for ACL graft rupture that have also been found to be risk factors for first-time injury. There were no risk factors in common between ACL graft injury and first-time ACL injury for males.

Project description:Cranial cruciate ligament rupture (CR) is a degenerative condition in dogs that typically has a non-contact mechanism. Subsequent contralateral rupture often develops in dogs with unilateral CR. Synovitis severity is an important factor that promotes ligament degradation. Consequently, we wished to evaluate the utility of arthroscopy for assessment of stifle synovitis in dogs with CR. Herein, we report results of a prospective study of 27 dogs with unilateral CR and bilateral radiographic osteoarthritis. Arthroscopic images and synovial biopsies from the lateral and medial joint pouches were obtained bilaterally and graded for synovial hypertrophy, vascularity, and synovitis. Synovial tartrate-resistant acid phosphatase-positive (TRAP+) macrophages, CD3(+) T lymphocytes, Factor VIII+ blood vessels, and synovial intima thickness were quantified histologically and related to arthroscopic observations. Risk of subsequent contralateral CR was examined using survival analysis. We found that arthroscopic scores were increased in the index stifle, compared with the contralateral stifle (p<0.05). Numbers of CD3+ T lymphocytes (SR = 0.50, p<0.05) and TRAP+ cells in joint pouches (SR = 0.59, p<0.01) were correlated between joint pairs. Arthroscopic grading of vascularity and synovitis was correlated with number density of Factor VIII+ vessels (SR>0.34, p<0.05). Arthroscopic grading of villus hypertrophy correlated with numbers of CD3(+) T lymphocytes (SR = 0.34, p<0.05). Synovial intima thickness was correlated with arthroscopic hypertrophy, vascularity, and synovitis (SR>0.31, p<0.05). Strong intra-observer and moderate inter-observer agreement for arthroscopic scoring was found. Dog age and arthroscopic vascularity significantly influenced risk of contralateral CR over time. We conclude that arthroscopic grading of synovitis is a precise tool that correlates with histologic synovitis. Arthroscopy is useful for assessment of stifle synovitis in client-owned dogs, and could be used in longitudinal clinical trials to monitor synovial responses to disease-modifying therapy.

Project description:BackgroundCranial cruciate ligament rupture (CCLR) is one of the most common causes of pelvic limb lameness in dogs. Risk factors for CCLR include breed (especially large and giant breeds), body weight, gender and spay/neuter status, and age. Few studies have evaluated physical activity and fitness indicators, however, as risk factors for disease. This study used an online questionnaire distributed primarily via social media to assess risk factors for CCLR in dogs actively engaged in agility training or competition to determine demographic and physical activity factors associated with rupture.ResultsData from 260 dogs with CCLR were compared to similar data from 1006 dogs without CCLR. All dogs were actively training or competing in agility at the time of CCLR or the time of data submission, respectively. Physical characteristics associated with increased risk of CCLR included younger age, spayed female sex, greater body weight, and greater weight to height ratio. Agility activities associated with increased odds ratios included competition in events sponsored by the North American Dog Agility Council (NADAC), competing at novice and intermediate levels, and competing in fewer than 10 events/year. Odds ratios were lower in dogs that competed in events sponsored by United Kingdom Agility International (UKI). Other activities associated with increased odds ratio for CCLR included involvement in flyball activities and short walks or runs over hilly or flat terrain on a weekly basis. Activities associated with decreased odds ratio included involvement in dock diving, barn hunt, nosework, or lure coursing/racing activities and participation in core balance and strength exercises at least weekly.ConclusionsThese results are consistent with previous studies demonstrating that body weight and spay/neuter status are risk factors for CCLR in dogs. This is the first report to demonstrate that risk of CCLR in agility dogs is decreased in dogs that engage in regular core strengthening exercises, compete more frequently, compete at higher levels, and compete in more athletically challenging venues.

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Genome-wide association analysis in dogs implicates 99 loci as risk variants for anterior cruciate ligament rupture.

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Genome-wide association analysis in dogs implicates 99 loci as risk variants for anterior cruciate ligament rupture.

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