Project Title:

Understanding the genetics of obesity- from GWAS to function in a canine model

Project Summary:

Obesity is a complex disease with high heritability in humans (40-70%). Genome wide association studies (GWAS) for body mass index (BMI) and related traits have led to the identification of >500 adiposity associated loci in humans, however, the polygenic nature of common obesity has limited researchers’ ability to pinpoint causative genes. The environmental factors implicated in human obesity (e.g. reduced exercise and high-energy foods) also impact their canine companions, approximately 59% of dogs are now overweight or obese. Dog breeds provide a powerful genetic model for the discovery of disease genes as genetic bottlenecks have led to a reduction in heterogeneity, extensive linkage disequilibrium (LD) and increased frequency of disease-variants.

Several biological pathways are implicated in the regulation of body weight including the hypothalamic leptin-melanocortin pathway. Severe obesity in humans is sometimes caused by mutations disrupting the function of genes in this pathway including leptin, its receptor, POMC and melanocortin receptors. Three mutations in melanocortin receptors have been identified in dogs with all three mutations significantly effecting melanocortin signalling in vitro. The first aim of my PhD measured the frequency of these mutations in pure and mixed breed dog populations. In the breeds with a good distribution of genotypes a meta-analysis was performed. The loss of function MC3R mutation, p.M320I, was associated with a reduction in body weight. The main aim of my PhD project will use fine mapped obesity associated loci from GWAS studies to pinpoint candidate variants and use cellular studies to infer function.