Canine genome-wide association study identifies DENND1B as an obesity gene in dogs and humans

Obesity is a far-reaching, heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed the first successful canine genome-wide association study for body condition score, a measure of obesity, in 241 Labrador retrievers, with a polygenic score replicated in 350 more. Using an innovative cross-species approach, we showed new canine obesity genes are also associated with rare and common forms of obesity in humans. The lead association in dogs was with rs24430444 within the gene DENN domain containing 1B (DENND1B). Each copy of the alternate allele was associated with ~7% greater body fat per allele. We demonstrate a novel role for this gene in regulating signaling and trafficking of melanocortin 4 receptor, a critical controller of energy homeostasis. Thus, canine genetics identified novel obesity genes and mechanisms relevant to both dogs and humans.