Background: The high heritability of obesity is well established and a plethora of genetic obesity associations in human populations are hard to prioritise for further study. In dogs, an obesity epidemic shares many features with that in people but selective breeding means gene mapping is relatively straightforward. We study pet dogs as a model for human disease using genomics coupled with follow-on molecular, epidemiological and physiological studies. Our overall aim is to understand the mechanistic links between genes and obesity in dogs and humans.   

Methods/Results: To identify genetic risk factors for obesity in Labradors we performed a GWAS study using linear mixed models in 241 Labradors. Obesity-associated loci reaching the genomic significance threshold were used to generate genomic risk scores that were predictive of obesity and body weight in an independent set of >250 Labradors and to a lesser extent in a related retriever breed, but not more distantly related breeds.  Genomic risk scores provide insight into variable penetrance of the POMC variant and explain why some sub-populations (assistance dogs and chocolate coat colour) have increased obesity risk. The data show genomic risk is in large part mediated via eating behaviour and we demonstrate genomic risk is moderated by environmental exposure to dietary risk factors and exercise.

Fine mapping was performed to focus on candidate obesity genes and variants in the Labrador GWAS. We interrogated human GWAS data from UK BioBank and the GIANT consortium and tested for rare variant enrichment in UK BioBank exomes and the SCOOP cohort of patients with early onset, severe obesity to show several genes identified as having a large effect in dogs are also associated with human obesity; these include SEMA3D, CSNK1A1, CDH8 and CARD11. Another such gene was DENND1B which we show affects endocytosis and trafficking of melanocortin 4 receptors in vitro, providing a novel mechanism underlying the obesity risk.

Conclusion: These data cement the value of dogs as a canine model of complex genetic disease and show how canine studies are of value to improve understanding of both canine and human obesity.  We propose several genes as priority candidates for study and propose a new mechanistic link between DENND1B and obesity.

Ethical Statement: The research was carried out in dogs (Canis familiaris) kept as pets or assistance dogs. DNA was extracted from oral swabs (saliva). Eating behaviour was assessed using an owner-reported questionnaire (Raffan 2015). Work was approved by the University of Cambridge Dept Veterinary Medicine Ethics and Welfare Review Committee.