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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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          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.

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          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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                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                July 2007
                20 July 2007
                31 May 2007
                : 3
                : 7
                [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@ (DS); goncalo@ (GRA)
                07-PLGE-RA-0253R2 plge-03-07-08
                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
                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



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