In flat-faced dog breeds, air resistance caused by skull conformation is believed to be a major determinant of Brachycephalic Obstructive Airway Syndrome (BOAS). The clinical presentation of BOAS is heterogeneous, suggesting determinants independent of skull conformation contribute to airway disease. Norwich Terriers, a mesocephalic breed, are predisposed to Upper Airway Syndrome (UAS), a disease whose pathological features overlap with BOAS. Our health screening clinic examined and scored the airways of 401 Norwich terriers by laryngoscopy. Genome-wide association analyses of UAS-related pathologies revealed a genetic association on canine chromosome 13 (rs9043975, p = 7.79×10 -16 ). Whole genome resequencing was used to identify causal variant(s) within a 414 kb critical interval. This approach highlighted an error in the CanFam3.1 dog assembly, which when resolved, led to the discovery of a c.2786G>A missense variant in exon 20 of the positional candidate gene, ADAM metallopeptidase with thrombospondin type 1 motif 3 ( ADAMTS3 ). In addition to segregating with UAS amongst Norwich Terriers, the ADAMTS3 c.2786G>A risk allele frequency was enriched among the BOAS-susceptible French and (English) Bulldogs. Previous studies indicate that ADAMTS3 loss of function results in lymphoedema. Our results suggest a new paradigm in the understanding of canine upper airway disease aetiology: airway oedema caused by disruption of ADAMTS3 predisposes dogs to respiratory obstruction. These findings will enhance breeding practices and could refine the prognostics of surgical interventions that are often used to treat airway obstruction. Author summary Respiratory diseases are prevalent across dog breeds, particularly in brachycephalic breeds such as the Bulldog and French bulldog. The flat facial conformation of these breeds has long been assumed to be the major predisposing factor, however, the underlying genetics of their respiratory condition has never been elucidated. We became interested in the Norwich Terrier, a breed presenting with many of the same respiratory disease symptoms as the Bulldog. A distinction, however, is that the Norwich terrier is not considered to be a brachycephalic breed and so presented an opportunity to dissociate respiratory disease from head conformation. We performed a genome-wide association analysis for respiratory disease severity in the Norwich Terrier and resolved an association on chromosome 13 to a missense mutation in ADAMTS3 . Variants in this gene were previously shown to cause an oedematous phenotype–a disease characteristic in the airways of affected Norwich Terriers and brachycephalic dogs alike. We screened over 100 breeds for the ADAMTS3 variant and found that it is enriched in the Norwich Terrier, Bulldog and French Bulldog. This discovery changes how we view respiratory disease predisposition in the dog, offers potential genetic screens and highlights a new biological function for ADAMTS3 .
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