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.