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

Forsberg SK, Kierczak M, Ljungvall I, Merveille AC, Gouni V, Wiberg M, Lundgren Willesen J, Hanås S, Lequarré AS, Mejer Sørensen L, Tiret L, McEntee K, Seppälä E, Koch J, Battaille G, Lohi H, Fredholm M, Chetboul V, Häggström J, Carlborg Ö, Lindblad-Toh K, Höglund K - PLoS ONE (2015)

Bottom Line: Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration.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.

View Article: PubMed Central - PubMed

Affiliation: Computational Genetics Section, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

Two-locus genotype-phenotype map for FructoCFA3 and the CFA5 locus with reduced heterozygosity in the Belgian shepherd breed.The CFA5 interactor genotype is given above and the FructoCFA3 genotype below the figure. The top panel includes only non-BS dogs, and the bottom panel only BS dogs. The proportion of phenotypic variance explained by FructoCFA3 and the p-value of the correlation, in every strata defined by the interactor, are shown at the bottom. The number of individuals in every group are shown in the center of the boxes.
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pone.0123173.g004: Two-locus genotype-phenotype map for FructoCFA3 and the CFA5 locus with reduced heterozygosity in the Belgian shepherd breed.The CFA5 interactor genotype is given above and the FructoCFA3 genotype below the figure. The top panel includes only non-BS dogs, and the bottom panel only BS dogs. The proportion of phenotypic variance explained by FructoCFA3 and the p-value of the correlation, in every strata defined by the interactor, are shown at the bottom. The number of individuals in every group are shown in the center of the boxes.

Mentions: To evaluate whether this locus on CFA5 interacted with the main effect locus FructoCFA3, we fitted a linear regression model including both loci using the data from the non-Belgian shepherd populations, i.e. where the BS-allele on CFA5 segregated at a lower frequency and where FructoCFA3 did not have an effect in the earlier GWAS analyses. An F-test comparing the fit of a model with additive effects only for the two loci to a model including also the interaction between them shows that the interaction model provides a significantly better fit to the data (p = 0.025). To explore the epistatic genotype-phenotype relationship in more detail, we stratified the data by CFA5 genotype and estimated the effect of FructoCFA3 in each of the three genotype-classes independently (Fig 4). Despite the lower number of individuals in the A/G (n = 43) and G/G (n = 75) genotype classes, the results show that the effect of the FructoCFA3 locus is larger in the presence of the G-allele that is predominant in the BS breed.


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

Forsberg SK, Kierczak M, Ljungvall I, Merveille AC, Gouni V, Wiberg M, Lundgren Willesen J, Hanås S, Lequarré AS, Mejer Sørensen L, Tiret L, McEntee K, Seppälä E, Koch J, Battaille G, Lohi H, Fredholm M, Chetboul V, Häggström J, Carlborg Ö, Lindblad-Toh K, Höglund K - PLoS ONE (2015)

Two-locus genotype-phenotype map for FructoCFA3 and the CFA5 locus with reduced heterozygosity in the Belgian shepherd breed.The CFA5 interactor genotype is given above and the FructoCFA3 genotype below the figure. The top panel includes only non-BS dogs, and the bottom panel only BS dogs. The proportion of phenotypic variance explained by FructoCFA3 and the p-value of the correlation, in every strata defined by the interactor, are shown at the bottom. The number of individuals in every group are shown in the center of the boxes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430432&req=5

pone.0123173.g004: Two-locus genotype-phenotype map for FructoCFA3 and the CFA5 locus with reduced heterozygosity in the Belgian shepherd breed.The CFA5 interactor genotype is given above and the FructoCFA3 genotype below the figure. The top panel includes only non-BS dogs, and the bottom panel only BS dogs. The proportion of phenotypic variance explained by FructoCFA3 and the p-value of the correlation, in every strata defined by the interactor, are shown at the bottom. The number of individuals in every group are shown in the center of the boxes.
Mentions: To evaluate whether this locus on CFA5 interacted with the main effect locus FructoCFA3, we fitted a linear regression model including both loci using the data from the non-Belgian shepherd populations, i.e. where the BS-allele on CFA5 segregated at a lower frequency and where FructoCFA3 did not have an effect in the earlier GWAS analyses. An F-test comparing the fit of a model with additive effects only for the two loci to a model including also the interaction between them shows that the interaction model provides a significantly better fit to the data (p = 0.025). To explore the epistatic genotype-phenotype relationship in more detail, we stratified the data by CFA5 genotype and estimated the effect of FructoCFA3 in each of the three genotype-classes independently (Fig 4). Despite the lower number of individuals in the A/G (n = 43) and G/G (n = 75) genotype classes, the results show that the effect of the FructoCFA3 locus is larger in the presence of the G-allele that is predominant in the BS breed.

Bottom Line: Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration.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.

View Article: PubMed Central - PubMed

Affiliation: Computational Genetics Section, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus