The Shepherds’ Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds

Abstract

Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (pcorrected ≈ 1:68 × 10-6) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

What's in a Name? Classification of Diabetes Mellitus in Veterinary Medicine and Why It Matters

“…To our knowledge, primary susceptibility genes for MODY in people have not been evaluated in dogs. A genome‐wide study identified a chromosomal locus associated with serum fructosamine concentrations in Belgian Shepherds . A causative mutation was not discovered, but positional genes involved in glucose metabolism and insulin signaling ( GAPDH and LETM ) were implicated.…”

Genome wide association study of 40 clinical measurements in eight dog breeds

“…The previous study used linear mixed models including a fixed effect for breed, while here we normalized raw phenotype values to minimize the effect of outliers for statistical analysis, used the GEMMA algorithm in each breed separately, and merged p values by binary effects model to account for existence of genetic effect (see Materials and Methods). Note that using the same data, a genome wide significant association on chromosome 3 (P = 1.68 × 10 −6 , P for permutation = 0.024) was reported in Belgium Shepherd 30 . In the current analysis, we observed a similar tendency, but it was not significant (P = 5.15 × 10 −6 ).…”

“…One SNP in this locus also explained a large proportion (11.2-45.8%) of the variance. Note that the previous GWAS focusing on fructosamine data of the same dogs did not identify any genome wide significant associations 29,30 . This difference could be explained by different analyses methods.…”

“…A total of 472 healthy dogs consisting of eight breeds (Belgian Shepherd, Cavalier King Charles Spaniel, Dachshund, Doberman, Finnish Lapphund, German Shepherd, Labrador Retriever, and Newfoundland) from five countries (Belgium, Denmark, Finland, France, and Sweden) were recruited for this study as part of the EU-funded LUPA project ( Supplementary Table S6) 42 . Our group previously reported GWAS focusing only on fructosamine using the same dogs 30 . However, using the binary effects model that was expected to increase the statistical power of the analysis, we have obtained a new association regarding fructosamine that is worth being reported in the present study.…”

Interbreed variation of biomarkers of lipid and glucose metabolism in dogs

“…Even though the different breed concentrations remained within the previously established RIs, our findings support the need for breed‐specific RIs for serum fructosamine concentrations. A previous article using the same dog population identified two loci involved in fructosamine regulation in BS . It was hypothesized that this finding could be connected to protective mechanisms against DM, a disease that is not frequently encountered in this breed.…”