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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<jats:italic>P<\/jats:italic>&lt;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 &lt;10% while 4 occurred at a frequency in the population ranging from 10\u201325%. 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 (<jats:italic>P<\/jats:italic>= 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 (<jats:italic>HoxA<\/jats:italic>), 28 (<jats:italic>NKX6-2)<\/jats:italic>, and 36 (<jats:italic>HoxD<\/jats:italic>). When analysis was limited to deletion CNVRs, the association was strengthened (<jats:italic>P<\/jats:italic>= 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0244075","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T19:06:49Z","timestamp":1609441609000},"page":"e0244075","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture"],"prefix":"10.1371","volume":"15","author":[{"given":"Emily E.","family":"Binversie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren A.","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne D.","family":"Engelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengling","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Moran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M.","family":"Piazza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susannah J.","family":"Sample","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0028-6005","authenticated-orcid":true,"given":"Peter","family":"Muir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,31]]},"reference":[{"key":"pone.0244075.ref001","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.2106\/JBJS.L.01705","article-title":"Societal and economic impact of anterior cruciate ligament tears","volume":"95","author":"RC Mather","year":"2013","journal-title":"J Bone Joint Surg Am"},{"key":"pone.0244075.ref002","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1016\/j.joca.2016.06.006","article-title":"Epidemiology of intra- and peri-articular structural injuries in traumatic knee joint hemarthrosis\u2013data from 1145 consecutive knees with subacute MRI.","volume":"24","author":"O Olsson","year":"2016","journal-title":"Osteoarthr Cartil."},{"key":"pone.0244075.ref003","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1177\/0363546514542796","article-title":"Incidence and trends of anterior cruciate ligament reconstruction in the United States.","volume":"42","author":"NA Mall","year":"2014","journal-title":"Am J Sports Med"},{"key":"pone.0244075.ref004","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1177\/0363546515626539","article-title":"Changes in knee osteoarthritis, symptoms, and function after anterior cruciate ligament reconstruction: A 20 year prospective follow-up study.","volume":"44","author":"MA Risberg","year":"2016","journal-title":"Am J Sports Med"},{"key":"pone.0244075.ref005","first-page":"537","article-title":"Important features associated with acute anterior cruciate ligament injury.","volume":"103","author":"PJ McNair","year":"1990","journal-title":"N Z Med J"},{"key":"pone.0244075.ref006","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1002\/jor.23441","article-title":"New perspectives on ACL injury: On the role of repetitive sub-maximal knee loading in causing ACL fatigue failure","volume":"34","author":"EM Wojtys","year":"2016","journal-title":"J Orthop Res"},{"key":"pone.0244075.ref007","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1177\/0363546512454414","article-title":"Survival of the anterior cruciate ligament graft and the contralateral ACL at a minimum of 15 years.","volume":"40","author":"HE Bourke","year":"2012","journal-title":"Am J Sports Med"},{"key":"pone.0244075.ref008","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1007\/s40279-017-0678-2","article-title":"Genetic variants and anterior cruciate ligament rupture: A systematic review.","volume":"47","author":"M Kaynak","year":"2017","journal-title":"Sports Med"},{"key":"pone.0244075.ref009","doi-asserted-by":"crossref","first-page":"3262","DOI":"10.1177\/0363546515624467","article-title":"Is there a genetic predisposition to anterior cruciate ligament tear? 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