197
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          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.

          Related collections

          Most cited references45

          • Record: found
          • Abstract: not found
          • Article: not found

          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            A genome-wide association study identifies novel risk loci for type 2 diabetes.

            Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old.

              Obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death, but the relation between overweight (a BMI of 25.0 to 29.9) and the risk of death has been questioned. We prospectively examined BMI in relation to the risk of death from any cause in 527,265 U.S. men and women in the National Institutes of Health-AARP cohort who were 50 to 71 years old at enrollment in 1995-1996. BMI was calculated from self-reported weight and height. Relative risks and 95 percent confidence intervals were adjusted for age, race or ethnic group, level of education, smoking status, physical activity, and alcohol intake. We also conducted alternative analyses to address potential biases related to preexisting chronic disease and smoking status. During a maximum follow-up of 10 years through 2005, 61,317 participants (42,173 men and 19,144 women) died. Initial analyses showed an increased risk of death for the highest and lowest categories of BMI among both men and women, in all racial or ethnic groups, and at all ages. When the analysis was restricted to healthy people who had never smoked, the risk of death was associated with both overweight and obesity among men and women. In analyses of BMI during midlife (age of 50 years) among those who had never smoked, the associations became stronger, with the risk of death increasing by 20 to 40 percent among overweight persons and by two to at least three times among obese persons; the risk of death among underweight persons was attenuated. Excess body weight during midlife, including overweight, is associated with an increased risk of death. Copyright 2006 Massachusetts Medical Society.
                Bookmark

                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
                : e115
                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
                efb96e55-3508-47a3-890c-ada3556d5da8
                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.
                History
                : 16 April 2007
                : 31 May 2007
                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
                Genetics

                Comments

                Comment on this article