Endocrine Abstracts

Obesity is a public health crisis for both man and man’s best friend: both human and canine obesity have increased significantly in the last thirty years, driving research to understand obesity genetics. Dogs are an ideal model organism to study mammalian obesity, given their shared physiology with humans. Pure-bred dogs have reduced genetic diversity due to population bottlenecks and artificial selection. Consequently, genomic regions under positive selection may carry “footprints” detectable as selective sweeps. As Labrador Retrievers are predisposed to obesity compared to other breeds, we hypothesized that obesogenic alleles may be fixed or nearly-fixed in Labradors but at low frequency or absent in low-risk breeds. We searched for signs of positive selection using selective sweep detection statistics, Tajima’s D and Integrated Haplotype Score, in 316 dogs’ SNP genotype data. We found 1829 genes in 83 possible regions of positive selection, which contained 16 obesity candidate genes, identified by comparison with literature. We prioritised genetic variants within those genes as candidates for obesity if they were significantly more common in Labradors than in breeds with low obesity risk (P < 0.05). We then tested their association with body condition score (BCS), food motivation, and weight, in 592 Labradors. Top candidate variants included a 3’UTR variant in MC4R. The wild-type allele was relatively-fixed in Labradors and significantly associated with food motivation. Secondly, a missense variant was found in NUDT16L1, an RNA-binding protein suppressing ciliogenesis. Labradors were relatively-fixed for the wild-type allele, which associated significantly with BCS. Finally, a 3’UTR variant in the adiponectin receptor ADIPOR1 correlated significantly with weight. We demonstrated the domestic dog’s unique population structure can facilitate identifying novel variants. We suggest methods of further investigation of candidate variants for canine obesity, in genes previously associated with human obesity, but in which variants have yet been found in humans or dogs.