Endocrine Abstracts

Background: Obesity is a global health concern and a recognised risk factor for several prevalent diseases. Genetic variation can influence susceptibility to the development of obesity. Existing work in humans explains a limited proportion of the heritability of obesity-related traits and prioritisation of variants on which to focus mechanistic studies is challenging. Novel insights can be obtained from species such as the domestic dog and the pig in which obesity occurs spontaneously and gene mapping is more tractable as a consequence of selective breeding.

Methods: A genome wide association study in 241 Labrador Retrievers identified obesity-associated loci harbouring 19 positional candidate genes which were subjected to a novel analysis pipeline designed to assess their plausibility in influencing obesity risk. Multiple lines of evidence were used including: i) the identification of statistically overrepresented signalling pathways; ii) tissue-specific expression data; iii) in vivo modelling databases; iv) data from existing human studies. In pigs, we interrogated publicly available data from GWAS and linkage studies of adipose related traits to focus on loci consistently associated with adipose accumulation.

Results: The Wnt signalling pathway was overrepresented amongst the canine candidate genes when compared to the genome as a whole (χ²(1, n=20700) = 16.5881, P< 0.000001), with csnk1a1, cdh8, and sdk1 falling within chromosomal regions of interest. Similarly, in pigs, the Wnt signalling-associated gene lrp5 was found within the chromosomal region most strongly associated with adiposity. This aligns with previously identified associations between obesity in humans and the gene lgr4, which encodes a receptor involved in Wnt signalling.

Conclusions: This investigation suggests that genetic variants within the Wnt signalling pathway may influence obesity risk in multiple species. This in silico approach will be supplemented with work in vitro and in vivo to determine how the Wnt signalling pathway may influence obesity risk.