Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans

Sameer Dinkar Pant; Peter Karlskov-Mortensen; Mette Juul Jacobsen; Susanna Cirera Salicio; Lisette Kogelman; Camilla Vibeke Sichlau Bruun; Thomas Mark; Claus Bøttcher Jørgensen; Niels Grarup; Emil Vincent Rosenbaum Appel; Ehm A. A. Galjatovic; Torben Hansen; Oluf Borbye Pedersen; Maryse Guerin; Thierry Huby; Philipppe Lesnik; Theo H. E. Meuwissen; Haja Kadarmideen; Merete Fredholm

doi:10.1371/journal.pone.0137356

Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans

Sameer Dinkar Pant, Peter Karlskov-Mortensen, Mette Juul Jacobsen, Susanna Cirera Salicio, Lisette Kogelman, Camilla Vibeke Sichlau Bruun, Thomas Mark, Claus Bøttcher Jørgensen, Niels Grarup, Emil Vincent Rosenbaum Appel, Ehm A. A. Galjatovic, Torben Hansen, Oluf Borbye Pedersen, Maryse Guerin, Thierry Huby, Philipppe Lesnik, Theo H. E. Meuwissen, Haja Kadarmideen, Merete Fredholm

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Abstract

The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits in the parental generation. Several obesity and metabolic phenotypes were recorded (n = 35) from birth to slaughter (242 ± 48 days), including body composition determined at about two months of age (63 ± 10 days) via dual-energy x-ray absorptiometry (DXA) scanning. All pigs were genotyped using Illumina Porcine 60k SNP Beadchip and a combined linkage disequilibrium-linkage analysis was used to identify genome-wide significant associations for collected phenotypes. We identified 229 QTLs which associated with adiposity- and metabolic phenotypes at genome-wide significant levels. Subsequently comparative analyses were performed to identify the extent of overlap between previously identified QTLs in both humans and pigs. The combined analysis of a large number of obesity phenotypes has provided insight in the genetic architecture of the molecular mechanisms underlying these traits indicating that QTLs underlying similar phenotypes are clustered in the genome. Our analyses have further confirmed that genetic heterogeneity is an inherent characteristic of obesity traits most likely caused by segregation or fixation of different variants of the individual components belonging to cellular pathways in different populations. Several important genes previously associated to obesity in human studies, along with novel genes were identified. Altogether, this study provides novel insight that may further the current understanding of the molecular mechanisms underlying human obesity.

Original language	English
Article number	e0137356
Journal	PLOS ONE
Volume	10
Issue number	9
Number of pages	22
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0137356
Publication status	Published - 8 Sept 2015

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Pant, S. D., Karlskov-Mortensen, P., Jacobsen, M. J., Cirera Salicio, S., Kogelman, L., Bruun, C. V. S., Mark, T., Jørgensen, C. B., Grarup, N., Appel, E. V. R., Galjatovic, E. A. A., Hansen, T., Pedersen, O. B., Guerin, M., Huby, T., Lesnik, P., Meuwissen, T. H. E., Kadarmideen, H., & Fredholm, M. (2015). Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans. PLOS ONE, 10(9), [e0137356]. https://doi.org/10.1371/journal.pone.0137356

Pant, SD , Karlskov-Mortensen, P , Jacobsen, MJ , Cirera Salicio, S , Kogelman, L , Bruun, CVS , Mark, T , Jørgensen, CB , Grarup, N, Appel, EVR, Galjatovic, EAA, Hansen, T, Pedersen, OB, Guerin, M, Huby, T, Lesnik, P, Meuwissen, THE, Kadarmideen, H & Fredholm, M 2015, 'Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans', PLOS ONE, vol. 10, no. 9, e0137356. https://doi.org/10.1371/journal.pone.0137356

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abstract = "The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits in the parental generation. Several obesity and metabolic phenotypes were recorded (n = 35) from birth to slaughter (242 ± 48 days), including body composition determined at about two months of age (63 ± 10 days) via dual-energy x-ray absorptiometry (DXA) scanning. All pigs were genotyped using Illumina Porcine 60k SNP Beadchip and a combined linkage disequilibrium-linkage analysis was used to identify genome-wide significant associations for collected phenotypes. We identified 229 QTLs which associated with adiposity- and metabolic phenotypes at genome-wide significant levels. Subsequently comparative analyses were performed to identify the extent of overlap between previously identified QTLs in both humans and pigs. The combined analysis of a large number of obesity phenotypes has provided insight in the genetic architecture of the molecular mechanisms underlying these traits indicating that QTLs underlying similar phenotypes are clustered in the genome. Our analyses have further confirmed that genetic heterogeneity is an inherent characteristic of obesity traits most likely caused by segregation or fixation of different variants of the individual components belonging to cellular pathways in different populations. Several important genes previously associated to obesity in human studies, along with novel genes were identified. Altogether, this study provides novel insight that may further the current understanding of the molecular mechanisms underlying human obesity.",

author = "Pant, {Sameer Dinkar} and Peter Karlskov-Mortensen and Jacobsen, {Mette Juul} and {Cirera Salicio}, Susanna and Lisette Kogelman and Bruun, {Camilla Vibeke Sichlau} and Thomas Mark and J{\o}rgensen, {Claus B{\o}ttcher} and Niels Grarup and Appel, {Emil Vincent Rosenbaum} and Galjatovic, {Ehm A. A.} and Torben Hansen and Pedersen, {Oluf Borbye} and Maryse Guerin and Thierry Huby and Philipppe Lesnik and Meuwissen, {Theo H. E.} and Haja Kadarmideen and Merete Fredholm",

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T1 - Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans

AU - Pant, Sameer Dinkar

AU - Karlskov-Mortensen, Peter

AU - Jacobsen, Mette Juul

AU - Cirera Salicio, Susanna

AU - Kogelman, Lisette

AU - Bruun, Camilla Vibeke Sichlau

AU - Mark, Thomas

AU - Jørgensen, Claus Bøttcher

AU - Grarup, Niels

AU - Appel, Emil Vincent Rosenbaum

AU - Galjatovic, Ehm A. A.

AU - Hansen, Torben

AU - Pedersen, Oluf Borbye

AU - Guerin, Maryse

AU - Huby, Thierry

AU - Lesnik, Philipppe

AU - Meuwissen, Theo H. E.

AU - Kadarmideen, Haja

AU - Fredholm, Merete

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N2 - The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits in the parental generation. Several obesity and metabolic phenotypes were recorded (n = 35) from birth to slaughter (242 ± 48 days), including body composition determined at about two months of age (63 ± 10 days) via dual-energy x-ray absorptiometry (DXA) scanning. All pigs were genotyped using Illumina Porcine 60k SNP Beadchip and a combined linkage disequilibrium-linkage analysis was used to identify genome-wide significant associations for collected phenotypes. We identified 229 QTLs which associated with adiposity- and metabolic phenotypes at genome-wide significant levels. Subsequently comparative analyses were performed to identify the extent of overlap between previously identified QTLs in both humans and pigs. The combined analysis of a large number of obesity phenotypes has provided insight in the genetic architecture of the molecular mechanisms underlying these traits indicating that QTLs underlying similar phenotypes are clustered in the genome. Our analyses have further confirmed that genetic heterogeneity is an inherent characteristic of obesity traits most likely caused by segregation or fixation of different variants of the individual components belonging to cellular pathways in different populations. Several important genes previously associated to obesity in human studies, along with novel genes were identified. Altogether, this study provides novel insight that may further the current understanding of the molecular mechanisms underlying human obesity.

AB - The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits in the parental generation. Several obesity and metabolic phenotypes were recorded (n = 35) from birth to slaughter (242 ± 48 days), including body composition determined at about two months of age (63 ± 10 days) via dual-energy x-ray absorptiometry (DXA) scanning. All pigs were genotyped using Illumina Porcine 60k SNP Beadchip and a combined linkage disequilibrium-linkage analysis was used to identify genome-wide significant associations for collected phenotypes. We identified 229 QTLs which associated with adiposity- and metabolic phenotypes at genome-wide significant levels. Subsequently comparative analyses were performed to identify the extent of overlap between previously identified QTLs in both humans and pigs. The combined analysis of a large number of obesity phenotypes has provided insight in the genetic architecture of the molecular mechanisms underlying these traits indicating that QTLs underlying similar phenotypes are clustered in the genome. Our analyses have further confirmed that genetic heterogeneity is an inherent characteristic of obesity traits most likely caused by segregation or fixation of different variants of the individual components belonging to cellular pathways in different populations. Several important genes previously associated to obesity in human studies, along with novel genes were identified. Altogether, this study provides novel insight that may further the current understanding of the molecular mechanisms underlying human obesity.

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DO - 10.1371/journal.pone.0137356

M3 - Journal article

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SN - 1932-6203

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JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 9

M1 - e0137356

ER -

Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans

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