The shepherds' tale: a genome-wide study across 9 dog breeds implicates two loci in the regulation of fructosamine serum concentration in Belgian shepherds

Simon K G Forsberg; Marcin Kierczak; Ingrid Ljungvall; Anne-Christine Merveille; Vassiliki Gouni; Maria Wiberg; Jakob Willesen; Sofia Hanås; Anne-Sophie Lequarré; Louise Mejer Sørensen; Laurent Tiret; Kathleen McEntee; Eija Seppälä; Jørgen Koch; Géraldine Battaille; Hannes Lohi; Merete Fredholm; Valerie Chetboul; Jens Häggström; Örjan Carlborg; Kerstin Lindblad-Toh; Katja Höglund

doi:10.1371/journal.pone.0123173

The shepherds' tale: a genome-wide study across 9 dog breeds implicates two loci in the regulation of fructosamine serum concentration in Belgian shepherds

Simon K G Forsberg, Marcin Kierczak, Ingrid Ljungvall, Anne-Christine Merveille, Vassiliki Gouni, Maria Wiberg, Jakob Willesen, Sofia Hanås, Anne-Sophie Lequarré, Louise Mejer Sørensen, Laurent Tiret, Kathleen McEntee, Eija Seppälä, Jørgen Koch, Géraldine Battaille, Hannes Lohi, Merete Fredholm, Valerie Chetboul, Jens Häggström, Örjan CarlborgKerstin Lindblad-Toh, Katja Höglund

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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.

Original language	English
Article number	e0123173
Journal	PLOS ONE
Volume	10
Issue number	5
Number of pages	17
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0123173
Publication status	Published - 13 May 2015

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Forsberg, S. K. G., Kierczak, M., Ljungvall, I., Merveille, A.-C., Gouni, V., Wiberg, M., Willesen, J., Hanås, S., Lequarré, A.-S., Mejer Sørensen, L., Tiret, L., McEntee, K., Seppälä, E., Koch, J., Battaille, G., Lohi, H., Fredholm, M., Chetboul, V., Häggström, J., ... Höglund, K. (2015). The shepherds' tale: a genome-wide study across 9 dog breeds implicates two loci in the regulation of fructosamine serum concentration in Belgian shepherds. PLOS ONE, 10(5), Article e0123173. https://doi.org/10.1371/journal.pone.0123173

Forsberg, SKG, Kierczak, M, Ljungvall, I, Merveille, A-C, Gouni, V, Wiberg, M, Willesen, J, Hanås, S, Lequarré, A-S, 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 2015, 'The shepherds' tale: a genome-wide study across 9 dog breeds implicates two loci in the regulation of fructosamine serum concentration in Belgian shepherds', PLOS ONE, vol. 10, no. 5, e0123173. https://doi.org/10.1371/journal.pone.0123173

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title = "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.",

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T2 - a genome-wide study across 9 dog breeds implicates two loci in the regulation of fructosamine serum concentration in Belgian shepherds

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AU - Ljungvall, Ingrid

AU - Merveille, Anne-Christine

AU - Gouni, Vassiliki

AU - Wiberg, Maria

AU - Willesen, Jakob

AU - Hanås, Sofia

AU - Lequarré, Anne-Sophie

AU - Mejer Sørensen, Louise

AU - Tiret, Laurent

AU - McEntee, Kathleen

AU - Seppälä, Eija

AU - Koch, Jørgen

AU - Battaille, Géraldine

AU - Lohi, Hannes

AU - Fredholm, Merete

AU - Chetboul, Valerie

AU - Häggström, Jens

AU - Carlborg, Örjan

AU - Lindblad-Toh, Kerstin

AU - Höglund, Katja

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N2 - 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.

AB - 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.

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DO - 10.1371/journal.pone.0123173

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M1 - e0123173

ER -

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

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