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.
Highlights
Obesity, a condition represented by excessive accumulation of body fat, incurs massive economic costs and predisposes individuals to a number of other diseases including diabetes, cardiovascular disorders and osteoarthritis [1, 2]
The overall aim of this study was to identify genetic determinants underlying a broad range of obesity phenotypes in a porcine resource population, and to evaluate the efficacy of using a porcine model of human obesity for genomic investigations
Göttingen minipigs are susceptible to diet-induced obesity, and by crossing them to commercial pig breeds that have been genetically selected for leanness over several generations, we aimed to maximize genetic variance for obesity phenotypes in the resultant F2 populations
Summary
A condition represented by excessive accumulation of body fat, incurs massive economic costs and predisposes individuals to a number of other diseases including diabetes, cardiovascular disorders and osteoarthritis [1, 2]. The etiology of obesity is highly complex and influenced by numerous factors including genetics and environmental factors such as diet and exercise. For a complex trait like obesity, animal models can aid and accelerate the identification of underlying genetic determinants. Advantages of animal models include the possibility to design populations with certain genetic characteristics and much better control over environmental factors. Findings from murine models of obesity have often failed to translate to humans largely due to pathophysiological differences [5]. Pigs are omnivores like humans, and unlike mice, exhibit almost all of the pathophysiological features related to obesity and metabolic syndrome in a relatively short time span [7]
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