Comparative Analyses of QTLs Influencing Obesity and Metabolic Phenotypes in Pigs and Humans.
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.
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Sameer D
SD
Pant
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Peter
P
Karlskov-Mortensen
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Mette J
MJ
Jacobsen
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Susanna
S
Cirera
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Lisette J A
LJ
Kogelman
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Camilla S
CS
Bruun
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Thomas
T
Mark
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Claus B
CB
Jørgensen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Niels
N
Grarup
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Emil V R
EV
Appel
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Ehm A A
EA
Galjatovic
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Torben
T
Hansen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Oluf
O
Pedersen
INSERM UMR_S 1166, Integrative Biology of Atherosclerosis Team, F-75013, Paris, France; Sorbonne Universités UPMC Univ Paris 06 UMR_S 1166, Integrative Biology of Atherosclerosis Team, F-75013, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, 75013, Paris, France.
Maryse
M
Guerin
INSERM UMR_S 1166, Integrative Biology of Atherosclerosis Team, F-75013, Paris, France; Sorbonne Universités UPMC Univ Paris 06 UMR_S 1166, Integrative Biology of Atherosclerosis Team, F-75013, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, 75013, Paris, France.
Thierry
T
Huby
INSERM UMR_S 1166, Integrative Biology of Atherosclerosis Team, F-75013, Paris, France; Sorbonne Universités UPMC Univ Paris 06 UMR_S 1166, Integrative Biology of Atherosclerosis Team, F-75013, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, 75013, Paris, France.
Philipppe
P
Lesnik
Institute of Animal and Agricultural Sciences, Norwegian University of Life Sciences, Ås, Norway.
Theo H E
TH
Meuwissen
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Haja N
HN
Kadarmideen
Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Merete
M
Fredholm
D015502:Absorptiometry, Photon; D000818:Animals; D001823:Body Composition / Q000235:genetics; D015992:Body Mass Index; D001947:Breeding; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008659:Metabolic Diseases / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D034421:Sus scrofa / Q000235:genetics*