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      Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI ( p = 8.6 ×10 7), hip circumference ( p = 3.4 × 10 8), and weight ( p = 9.1 × 10 7). In Sardinia, homozygotes for the rare “G” allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common “A” allele. Within the PFKP gene, rs6602024 showed very strong association with BMI ( p = 4.9 × 10 6). Homozygotes for the rare “A” allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common “G” allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans ( N = 1,496) and in Hispanic Americans ( N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI ( p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight ( p = 0.001), and hip circumference ( p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare “A” allele were, on average, 1.0–3.0 BMI units heavier than homozygotes for the more common “G” allele. In summary, we have completed a whole genome–association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.

          Author Summary

          Although twin and family studies have clearly shown that genes play a role in obesity, it has proven quite difficult to identify the specific genetic variants involved. Here, we take advantage of recent technical and methodological advances to examine the role of common genetic variants on several obesity-related traits. By examining >4,000 Sardinians, we show that a specific genetic variant, rs9930506, and other nearby variants on human Chromosome 16 are associated with body mass index, hip circumference, and total body weight. The variants overlap FTO, a gene with poorly understood function. Further studies of the region may implicate new biological pathways affecting susceptibility to obesity. We also show that the association is not restricted to Sardinia but is also seen in independent samples of European Americans and Hispanic Americans. This finding is particularly important because obesity is associated with increased risk of cardiovascular disease and diabetes.

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          Most cited references 52

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            The tissue-specific pattern of mRNA expression can indicate important clues about gene function. High-density oligonucleotide arrays offer the opportunity to examine patterns of gene expression on a genome scale. Toward this end, we have designed custom arrays that interrogate the expression of the vast majority of protein-encoding human and mouse genes and have used them to profile a panel of 79 human and 61 mouse tissues. The resulting data set provides the expression patterns for thousands of predicted genes, as well as known and poorly characterized genes, from mice and humans. We have explored this data set for global trends in gene expression, evaluated commonly used lines of evidence in gene prediction methodologies, and investigated patterns indicative of chromosomal organization of transcription. We describe hundreds of regions of correlated transcription and show that some are subject to both tissue and parental allele-specific expression, suggesting a link between spatial expression and imprinting.
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              The prevalence of overweight in children and adolescents and obesity in adults in the United States has increased over several decades. To provide current estimates of the prevalence and trends of overweight in children and adolescents and obesity in adults. Analysis of height and weight measurements from 3958 children and adolescents aged 2 to 19 years and 4431 adults aged 20 years or older obtained in 2003-2004 as part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. Data from the NHANES obtained in 1999-2000 and in 2001-2002 were compared with data from 2003-2004. Estimates of the prevalence of overweight in children and adolescents and obesity in adults. Overweight among children and adolescents was defined as at or above the 95th percentile of the sex-specific body mass index (BMI) for age growth charts. Obesity among adults was defined as a BMI of 30 or higher; extreme obesity was defined as a BMI of 40 or higher. In 2003-2004, 17.1% of US children and adolescents were overweight and 32.2% of adults were obese. Tests for trend were significant for male and female children and adolescents, indicating an increase in the prevalence of overweight in female children and adolescents from 13.8% in 1999-2000 to 16.0% in 2003-2004 and an increase in the prevalence of overweight in male children and adolescents from 14.0% to 18.2%. Among men, the prevalence of obesity increased significantly between 1999-2000 (27.5%) and 2003-2004 (31.1%). Among women, no significant increase in obesity was observed between 1999-2000 (33.4%) and 2003-2004 (33.2%). The prevalence of extreme obesity (body mass index > or =40) in 2003-2004 was 2.8% in men and 6.9% in women. In 2003-2004, significant differences in obesity prevalence remained by race/ethnicity and by age. Approximately 30% of non-Hispanic white adults were obese as were 45.0% of non-Hispanic black adults and 36.8% of Mexican Americans. Among adults aged 20 to 39 years, 28.5% were obese while 36.8% of adults aged 40 to 59 years and 31.0% of those aged 60 years or older were obese in 2003-2004. The prevalence of overweight among children and adolescents and obesity among men increased significantly during the 6-year period from 1999 to 2004; among women, no overall increases in the prevalence of obesity were observed. These estimates were based on a 6-year period and suggest that the increases in body weight are continuing in men and in children and adolescents while they may be leveling off in women.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                pgen
                plge
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                July 2007
                20 July 2007
                31 May 2007
                : 3
                : 7
                Affiliations
                [1 ] Unità Operativa Geriatria, Istituto per la Patologia Endocrina e Metabolica, Rome, Italy
                [2 ] Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America
                [3 ] Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America
                [4 ] Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy
                [5 ] Unità Operativa Semplice Cardiologia, Divisione di Medicina, Presidio Ospedaliero Santa Barbara, Iglesias, Italy
                [6 ] Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [7 ] Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America
                [8 ] Department of Preventive Medicine and Epidemiology, Loyola Stritch School of Medicine, Chicago, Illinois, United States of America
                [9 ] Institut Scientifique et Technique de la Nutrition et de l'Alimentation, Paris, France
                [10 ] INSERM, U557 (UMR INSERM/INRA/CNAM), Paris, France
                Stanford University School of Medicine, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: schlessingerd@ 123456grc.nia.nih.gov (DS); goncalo@ 123456umich.edu (GRA)
                Article
                07-PLGE-RA-0253R2 plge-03-07-08
                10.1371/journal.pgen.0030115
                1934391
                17658951
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                Page count
                Pages: 11
                Categories
                Research Article
                Diabetes and Endocrinology
                Genetics and Genomics
                Genetics and Genomics
                Homo (Human)
                Custom metadata
                Scuteri A, Sanna S, Chen W, Uda M, Albai G, et al. (2007) Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3(7): e115. doi: 10.1371/journal.pgen.0030115

                Genetics

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