title: 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.
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Baker
authors.affiliation: Department of Animal Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Kirkpatrick
authors.affiliation: Department of Animal Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Guilherme J M
authors.initials: GJ
authors.lastname: Rosa
authors.affiliation: Department of Animal Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gianola
authors.affiliation: Department of Animal Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Dairy Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Bruno
authors.initials: B
authors.lastname: Valente
authors.affiliation: Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Sumner
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University, Corvalis, Oregon, United States of America.
authors.forename: Wendy
authors.initials: W
authors.lastname: Baltzer
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Zhengling
authors.initials: Z
authors.lastname: Hao
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Binversie
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Nicola
authors.initials: N
authors.lastname: Volstad
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Piazza
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Susannah J
authors.initials: SJ
authors.lastname: Sample
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0003-0028-6005
authors.initials: P
authors.lastname: Muir
mesh_terms: D053674:Aggrecans / Q000235:genetics; D000818:Animals; D016118:Anterior Cruciate Ligament / Q000473:pathology*; D000070598:Anterior Cruciate Ligament Injuries / Q000235:genetics*; D004285:Dogs; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D037181:Lectins, C-Type / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012421:Rupture / Q000235:genetics*
chemical_list: D053674:Aggrecans; D037181:Lectins, C-Type