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.
Highlights
Anterior cruciate ligament (ACL) rupture can be devastating and life changing, in young adults, as there is a 78% risk of knee arthritis after ACL rupture that is not influenced by surgical treatment [1]
We present a genome-wide association study (GWAS) in the domestic dog to discover additional candidate loci associated with ACL rupture
By undertaking a within-breed GWAS in the Labrador Retriever, we found 99 regions of association with the trait, suggesting that ACL rupture is a complex, potentially highly polygenic condition
Summary
Anterior cruciate ligament (ACL) rupture can be devastating and life changing, in young adults, as there is a 78% risk of knee arthritis after ACL rupture that is not influenced by surgical treatment [1]. The incidence of ACL rupture is high; it is estimated at 33.3–36.9/100,000 person years [2,3]. About 80,000 ACL graft surgeries are performed per year in the USA [4], with annual costs of approximately $1 billion [4]. Risk of contralateral rupture is high at 11.8% of patients [5]. Physiological and anatomic factors, such as intercondylar notch shape and posterior tibial slope influence disease risk and risk of ACL rupture. Subsequent contralateral ACL rupture is more frequent in females [6]. The underlying mechanism has not been fully defined, it is widely accepted that ACL rupture is a complex disorder with both genetic and environmental contributions to disease risk [7]. Given the prevalence of ACL rupture in human beings and substantial morbidity associated with the condition, identification of individuals at risk of ACL rupture before they become patients would provide the opportunity to intervene, thereby reducing the overall incidence of ACL rupture, the number of surgical procedures performed, and costs to both the hospital and patient
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