Obesity is a highly heritable yet complex condition whose genetic underpinnings remain challenging to fully elucidate. Dogs represent a particularly valuable genetic model for human obesity due to shared environmental influences and breed-specific genetic structures that facilitate robust trait mapping. In this study, we aimed to identify genetic loci associated with obesity using a canine model to provide novel insights into the genetic mechanisms underlying human obesity. Utilising breed-average obesity phenotypes derived from electronic health records of approximately 2.6 million dogs, we performed a multi-breed genome-wide association study (GWAS) encompassing 300 dogs from 36 breeds representing extensive genomic diversity.
Our study identified 19 independent loci significantly associated with obesity (Bonferroni-corrected significance threshold p = 1.28e-05). Fine-mapping using Bayesian Sum of Single Effects (SuSiE) identified high-confidence credible sets (Posterior Inclusion Probability, PIP = 99%). Most lead SNPs were intergenic or intronic, suggesting regulatory functions. Proximal candidate genes included CASP12 (CFA5), LEP (CFA14), GUCY1B1 (CFA15), GPD1L (CFA23), SRXN1 (CFA24), ETV6 (CFA27), COL25A1 (CFA32), EPHB3 (CFA34), and BLOC1S5 (CFA35).
The most significant association mapped to chromosome 13 (lead SNP 13:9231605), a region harbouring R-spondin 2 (RSPO2). RSPO2 is known to cause the “furnishings” coat phenotype in dogs. A complementary GWAS for furnishings corroborated this locus (lead SNP 13:8870149, p=3.45e-60). Bayesian colocalisation analysis using coloc.susie strongly suggested a shared causal variant for both obesity and furnishings at this locus (PP4 = 83.3%), supported by high LD (r2=0.99) between their lead SNPs and substantial overlap in credible sets. RSPO2 is a potent modulator of Wnt signalling, a pathway implicated in adipogenesis and potentially hypothalamic energy balance control. The shared genetics between a morphological trait (furnishings) and a metabolic trait (obesity risk) at RSPO2 highlights how selection for morphological traits may inadvertently influence metabolic processes via pleiotropic gene action.
These findings highlight the translational potential of canine genetic studies in elucidating human obesity biology. The link between RSPO2, Wnt signalling, and adiposity provides novel avenues for exploring metabolic regulation and potential therapeutic targets in both canines and humans.