Genetic determinants of common obesity and their value in prediction

MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Best Practice & Research: Clinical Endocrinology & Metabolism (Impact Factor: 4.6). 04/2012; 26(2):211-26. DOI: 10.1016/j.beem.2011.11.003
Source: PubMed

ABSTRACT Genome-wide association studies (GWAS) have revolutionised the discovery of genes for common traits and diseases, including obesity-related traits. In less then four years time, 52 genetic loci were identified to be unequivocally associated with obesity-related traits. This vast success raised hope and expectations that genetic information would become soon an integral part of personalised medicine. However, these loci have only small effects on obesity-susceptibility and explain just a fraction of the total variance. As such, their accuracy to predict obesity is poor and not competitive with the predictive ability of traditional risk factors. Nevertheless, some of these loci are being used in commercially available personal genome tests to estimate individuals' lifetime risk of obesity. While proponents believe that personal genome profiling could have beneficial effects on behaviour, early reports do not support this hypothesis. To conclude, the most valuable contribution of GWAS-identified loci lies in their contribution to elucidating new physiological pathways that underlie obesity-susceptibility.

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    • "The first GWAS-derived loci detected were intronic variants in the FTO (fat mass and obesity-associated) gene (Frayling et al. 2007; Dina et al. 2007) and variants approximately 200 kb downstream of MC4R (Loos et al. 2008). To date, more than 50 genetic loci relevant for body weight regulation have been identified by GWAS approaches (Loos 2012). While GWAS-associated signals are often identified by the name of the nearest gene, there is little evidence to suggest that variation in these specific genes explains the association signal. "
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    ABSTRACT: Body weight is a highly heritable trait across species. In humans, genetic variation plays a major role in determining the inter-individual differences in susceptibility or resistance to environmental factors which influence energy intake and expenditure. In this review, I discuss how genetic studies have contributed to our understanding of the central pathways that govern energy homeostasis. The study of individuals harboring highly penetrant genetic variants that disrupt the leptin-melanocortin pathway has informed our understanding of the physiological pathways involved in mammalian energy homeostasis.
    Mammalian Genome 08/2014; 25(9-10). DOI:10.1007/s00335-014-9541-z · 3.07 Impact Factor
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    • "Genome-wide association studies (GWAS) of obese people indicated about 50 genes to be involved in body weight regulation [28]. One of these genes is the Fat mass and obesity associated gene FTO. "
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    ABSTRACT: The metabolic syndrome is a worldwide problem mainly caused by obesity. FTO was found to be a obesity-risk gene in humans and FTO deficiency in mice led to reduction in adipose tissue. Thus, FTO is an important factor for the development of obesity. Leptin-deficient mice are a well characterized model for analysing the metabolic syndrome. To determine the relevance of FTO for the development of the metabolic syndrome we analysed different parameters in combined homozygous deficient mice (Lepob/ob;Fto-/-). Lepob/ob;Fto-/- mice showed an improvement in analysed hallmarks of the metabolic syndrome in comparison to leptin-deficient mice wild type or heterozygous for Fto. Lepob/ob;Fto-/- mice did not develop hyperglycaemia and showed an improved glucose tolerance. Furthermore, extension of beta-cell mass was prevented in Lepob/ob;Fto-/-mice and accumulation of ectopic fat in the liver was reduced. In conclusion this study demonstrates that FTO deficiency has a protective effect not only on the development of obesity but also on the metabolic syndrome. Thus, FTO plays an important role in the development of metabolic disorders and is an interesting target for therapeutic agents.
    PLoS ONE 08/2014; 9(8):e105349. DOI:10.1371/journal.pone.0105349 · 3.23 Impact Factor
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    • "Until now, at least 52 loci associated with obesity risk and obesity-related traits have been identified through GWAS [8]. Since 2007, an association between FTO single nucleotide polymorphisms (SNPs) and body mass index (BMI) and the risk of obesity had been identified in multiple populations, including adolescents and children. "
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    ABSTRACT: Background Previous studies have suggested that fat mass-and obesity-associated (FTO) gene is associated with body mass index (BMI) and the risk of obesity. This study aims to assess the association of five FTO polymorphisms (rs9939609, rs8050136, rs1558902, rs3751812 and rs6499640) with obesity and relative parameters in Han Chinese adolescents. Methods We examined a total of 401 adolescents, 223 normal weights (58.7% boys, 41.3% girls), 178 overweight (60.1% boys, 39.9% girls), aging from 14 to 18-years-old, recruited randomly from public schools in the central region of Wuxi, a southern city of China. DNA samples were genotyped for the five polymorphisms by Sequenom Plex MassARRAY. Association of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC) were investigated. Results 1) Serum FPG, FIns, TG and TC were statistically significant higher than that in normal control group. 2) We found that BMI was higher in the rs9939609 TA+AA, rs8050136 AC+AA, rs1558902 TA+AA and rs3751812 GT+TT genotypes than in wild TT genotypes (rs9939609: P = 0.038; rs1558902: P = 0.038;), CC genotypes(rs8050136: P = 0.024) and GG genotypes (rs3751812: P = 0.024), which were not significant on adjusting for multiple testing. 3) In case-control studies, five polymorphisms were not significantly associated with overweight (p>0.05), haplotype analyses showed non-haplotype is significantly associated with a higher risk of being overweight (p>0.05). 4) There existed no significant statistical difference about FPG, FIns, TG and TC in genotype model for any SNP. Conclusions Our study has conducted a genetic association study of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC). Our study found BMI of subjects with A allele of FTO rs9939609 is higher than that with T allele. Further studies on other polymorphisms from FTO and increasing the sample size are needed.
    PLoS ONE 06/2014; 9(6):e98984. DOI:10.1371/journal.pone.0098984 · 3.23 Impact Factor
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