BackgroundIn human beings, the heritability of obesity is estimated at 40–70%, but only a small proportion (<3%) of the genetic variants that account for naturally occurring obesity have been discovered. In dogs, selective breeding from small founder populations has led to trait-associated genes being concentrated within breeding populations, making dogs an appealing model for genetic study. Labrador retriever dogs are commonly prone to obesity and are highly food motivated; such a high prevalence within the breed suggests a genetic predisposition. The aim of this study was to discover the genetic basis of obesity in Labrador retriever dogs. MethodsPet dogs were prospectively selected for study. Body condition score was used to initially group them as lean or obese. They were further divided into two groups—obese, highly food-motivated dogs; and lean, non-food-motivated dogs—by a combination of a standardised questionnaire to owners and a veterinary surgeon taking a clinical and behavioural history. The coding sequence of AGRP, POMC, and MC4R were sequenced in several dogs from each group. Findings35 dogs (15 obese, 20 lean) were studied. The coding sequence of AGRP was normal in all dogs. Six single nucleotide polymorphisms (SNPs) were identified in MC4R, and eight SNPs and two deletions (one coding, one intronic) were found in POMC. There was no significant difference in the distribution of these variants between lean and obese groups for any of the variants except the coding deletion in POMC. Of 15 obese, food-motivated dogs, that deletion was heterozygous in eight and homozygous in two; the deletion was heterozygous in two of the 20 lean, non-food-motivated dogs. The association with obesity and high food motivation was significant (p=0·001). InterpretationMelanocortin signalling has a key role in normal energy homoeostasis; POMC is a precursor protein whose cleavage products act on MC4 and MC3 receptors to suppress appetite and increase energy expenditure. The deletion of 14 base pairs in exon 3 of POMC is predicted to disrupt the POMC protein, stopping production of its cleavage products β-melanocyte-stimulating hormone and β-endorphin and is therefore a strong candidate for causing much or all of the obesity susceptibility in Labrador retriever dogs. Further genetic studies are in progress to assess the prevalence of the deletion in larger cohorts of dogs from the same and different breeds, with functional studies also planned. FundingWellcome Trust, UK Medical Research Council, NIHR Cambridge Biomedical Research Centre.