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Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution

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PLoS Genetics

Public Library of Science

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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

      To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10 −11) and MSRA (WC, P = 8.9×10 −9). A third locus, near LYPLAL1, was associated with WHR in women only ( P = 2.6×10 −8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.

      Author Summary

      Here, we describe a meta-analysis of genome-wide association data from 38,580 individuals, followed by large-scale replication (in up to 70,689 individuals) designed to uncover variants influencing anthropometric measures of central obesity and fat distribution, namely waist circumference (WC) and waist–hip ratio (WHR). This work complements parallel efforts that have been successful in defining variants impacting overall adiposity and focuses on the visceral fat accumulation which has particularly strong relationships to metabolic and cardiovascular disease. Our analyses have identified two loci ( TFAP2B and MSRA) associated with WC, and a further locus, near LYPLAL1, which shows gender-specific relationships with WHR (all to levels of genome-wide significance). These loci vary in the strength of their associations with overall adiposity, and LYPLAL1 in particular appears to have a specific effect on patterns of fat distribution. All in all, these three loci provide novel insights into human physiology and the development of obesity.

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      Most cited references 51

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      A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.

      Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
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        A new multipoint method for genome-wide association studies by imputation of genotypes.

        Genome-wide association studies are set to become the method of choice for uncovering the genetic basis of human diseases. A central challenge in this area is the development of powerful multipoint methods that can detect causal variants that have not been directly genotyped. We propose a coherent analysis framework that treats the problem as one involving missing or uncertain genotypes. Central to our approach is a model-based imputation method for inferring genotypes at observed or unobserved SNPs, leading to improved power over existing methods for multipoint association mapping. Using real genome-wide association study data, we show that our approach (i) is accurate and well calibrated, (ii) provides detailed views of associated regions that facilitate follow-up studies and (iii) can be used to validate and correct data at genotyped markers. A notable future use of our method will be to boost power by combining data from genome-wide scans that use different SNP sets.
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          Merlin--rapid analysis of dense genetic maps using sparse gene flow trees.

          Efforts to find disease genes using high-density single-nucleotide polymorphism (SNP) maps will produce data sets that exceed the limitations of current computational tools. Here we describe a new, efficient method for the analysis of dense genetic maps in pedigree data that provides extremely fast solutions to common problems such as allele-sharing analyses and haplotyping. We show that sparse binary trees represent patterns of gene flow in general pedigrees in a parsimonious manner, and derive a family of related algorithms for pedigree traversal. With these trees, exact likelihood calculations can be carried out efficiently for single markers or for multiple linked markers. Using an approximate multipoint calculation that ignores the unlikely possibility of a large number of recombinants further improves speed and provides accurate solutions in dense maps with thousands of markers. Our multipoint engine for rapid likelihood inference (Merlin) is a computer program that uses sparse inheritance trees for pedigree analysis; it performs rapid haplotyping, genotype error detection and affected pair linkage analyses and can handle more markers than other pedigree analysis packages.
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            Author and article information

            Affiliations
            [1 ]Wellcome Trust Centre for Human Genetics, University of Oxford, , Oxford, United Kingdom
            [2 ]Institute of Epidemiology, Helmholtz Zentrum München, National Research Center for Environment and Health, Neuherberg, Germany
            [3 ]Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
            [4 ]Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
            [5 ]deCODE Genetics, Reykjavik, Iceland
            [6 ]Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America
            [7 ]Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
            [8 ]Department of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
            [9 ]Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, Massachusetts, United States of America
            [10 ]Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America
            [11 ]Oxford Centre for Diabetes, Department of Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
            [12 ]Medical Genetics, Clinical Pharmacology and Discovery Medicine, King of Prussia, Pennsylvania, United States of America
            [13 ]Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America
            [14 ]Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
            [15 ]Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
            [16 ]Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
            [17 ]Department of Epidemiology and Public Health, Imperial College London, London, United Kingdom
            [18 ]MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
            [19 ]Divisions of Genetics and Endocrinology, Program in Genomics, Children's Hospital, Boston, Massachusetts, United States of America
            [20 ]Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
            [21 ]Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari, Italy
            [22 ]The MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom
            [23 ]Department of Clinical Sciences, Diabetes, and Endocrinology Research Unit, University Hospital Malmö, Lund University, Malmö, Sweden
            [24 ]Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy
            [25 ]Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California, United States of America
            [26 ]National Human Genome Research Institute, Bethesda, Maryland, United States of America
            [27 ]Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America
            [28 ]Department of Epidemiology and Public Health, Imperial College London, London, United Kingdom
            [29 ]MRC Epidemiology Resource Centre, University of Southampton, Southampton, United Kingdom
            [30 ]Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
            [31 ]BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
            [32 ]Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
            [33 ]Department of Social Medicine, University of Bristol, Bristol, United Kingdom
            [34 ]Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, United States of America
            [35 ]Centre for Human Nutrition, University of Texas Southwestern Medical Centre, Dallas, Texas, United States of America
            [36 ]Division of Community Health Sciences, St George's University of London, London, United Kingdom
            [37 ]Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
            [38 ]KTL-National Public Health Institute, Helsinki, Finland
            [39 ]Division of Human Genetics, University of Southampton, Southampton, United Kingdom
            [40 ]Folkhälsan Research Center, Malmska Municipal Health Center and Hospital, Jakobstad, Finland
            [41 ]Department of Medicine, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
            [42 ]Finnish Institute of Occpational Health, Oulu, Finland
            [43 ]Centre National de Genotypage, Evry, France
            [44 ]The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
            [45 ]Department of Surgical and Perioperative Sciences, Section for Sports Medicine, Umeå University, Umeå, Sweden
            [46 ]Department of Community Medicine and Rehabilitation, Section of Geriatrics, Umeå University Hospital, Umeå, Sweden
            [47 ]Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
            [48 ]Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
            [49 ]Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom
            [50 ]Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden
            [51 ]Department of Clinical Chemistry, University of Oulu, Oulu, Finland
            [52 ]Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
            [53 ]Unita' Operativa Geriatrica, Instituto Nazionale Ricovero e Cura per Anziani (INRCA) IRCCS, Rome, Italy
            [54 ]Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
            [55 ]Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland
            [56 ]Department of Medicine and Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
            [57 ]Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, United Kingdom
            [58 ]Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, Bethesda, Maryland, United States of America
            [59 ]Ealing Hospital, Ealing Hospital National Health Service Trust, Southall, London, United Kingdom
            [60 ]Bristol Genetic Epidemiology Laboratories, Department of Social Medicine, University of Bristol, Bristol, United Kingdom
            [61 ]Department of Public Health and Clinical Medicine, Section for Nutritional Research (Umeå Medical Biobank), Umeå University, Umeå, Sweden
            [62 ]Institute of Health Sciences, University of Oulu, Biocenter Oulu, University of Oulu, Oulu, Finland
            [63 ]Department of Child and Adolescent Health, National Public Health Institute, Oulu, Finland
            [64 ]National Heart and Lung Institute, Imperial College London Hammersmith Hospital, London, United Kingdom
            [65 ]Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of Ameica
            [66 ]Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom
            [67 ]Medstar Research Institute, Baltimore, Maryland, United States of America
            [68 ]Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
            [69 ]Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, United Kingdom
            [70 ]Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
            [71 ]Broad Institute of MIT and Harvard, Boston, Massachusetts, United States of America
            [72 ]Faculty of Medicine, University of Iceland, Reykjavík, Iceland
            [73 ]Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America
            [74 ]Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America
            [75 ]National Institute for Health Research, Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
            University of Alabama at Birmingham, United States of America
            Author notes

            Conceived and designed the experiments: C. Lindgren, I. Heid, J. Randall., C. Lamina, V. Steinthorsdottir, L. Peltonen, I. Barroso, M. McCarthy. Performed the experiments: J. Zhao, A. Bennett, G. Crawford, A. Dominiczak, C. Groves, C. Guiducci, F. Payne, J. Peden, L. Scott, K. Silander, H. Stringham, T. Tuomi, M. Uda, P. Vollenweider, G. Waeber, J. Witteman. Analyzed the data: C. Lindgren, I. Heid, J. Randall., C. Lamina, V. Steinthorsdottir., L. Qi, E. Speliotes, G. Thorleifsson, C. Willer, B. Herrera, A. Jackson, N. Lim, P. Scheet, N. Soranzo, N. Amin, Y. Aulchenko, J. Chambers, A. Drong, J. Luan, H. Lyon, F. Rivadeneira, S. Sanna, N. Timpson, M. Zillikens, P. Almgren, S. Bandinelli, A. Bennett, R. Bergman, L. Bonnycastle, S. Bumpstead, S. Chanock, L. Cherkas, P. Chines, L. Coin, C. Cooper, G. Crawford, A. Doering, A. Dominiczak, A. Doney, S. Ebrahim, P. Elliott, M. Erdos, K. Estrada, L. Ferrucci, G. Fischer, N. Forouhi, C. Gieger, H. Grallert, C. Groves, S. Grundy, C. Guiducci, D. Hadley, A. Hamsten, A. Havulinna, A. Hofman, R. Holle, J. Holloway, T. Illig, B. Isomaa, L. Jacobs, K. Jameson, P. Jousilahti, J. Kuusisto, J. Laitinen, G. Lathrop, D. Lawlor, M. Mangino, W. McArdle, T. Meitinger, M. Morken, A. Morris, P. Munroe, N. Narisu, Anna Nordström, P. Nordström, B. Oostra, C. Palmer, F. Payne, J. Peden, I. Prokopenko, F. Renström, A. Ruokonen, M. Sandhu, L. Scott, A. Scuteri, K. Silander, K. Song, X. Yuan, H. Stringham, A. Swift, C. Wallace, G. Walters, M. Weedon, C. Zhang, W. Zhang, A. Kong, D. Strachan, T. Tanaka, C. Van Duijn, D. Waterworth, T. Frayling, R. Loos. Contributed reagents/materials/analysis tools: S. Chanock, L. Cherkas, P. Chines, C. Cooper, A. Doering, A. Doney, S. Ebrahim, A. Hamsten, B. Isomaa, P. Jousilahti, F. Karpe, J. Kuusisto, J. Laitinen, G. Lathrop, D. Lawlor, T. Meitinger, A. Morris, P. Munroe, A. Nordström, P. Nordström, B. Oostra, C. Palmer, F. Renström, A. Ruokonen, V. Salomaa, M. Sandhu, A. Scuteri, A. Swift, T. Tuomi, M. Uda, P. Vollenweider, G. Waeber, J. Witteman, M. Caulfield, F. Collins, G. Davey Smith, I. Day, P. Franks, A. Hattersley, F. Hu, M-R. Jarvelin, A. Kong, J. Kooner, M. Laakso, E. Lakatta, V. Mooser, A. Morris, L. Peltonen, N. Samani, T. Spector, D. Strachan, T. Tanaka, J. Tuomilehto, A. Uitterlinden, C. Van Duijn, N. Wareham, H. Watkins, D. Waterworth, M. Boehnke, P. Deloukas, L. Groop, D. Hunter, U.Thorsteinsdottir, D. Schlessinger, H. Wichmann, T. Frayling, G. Abecasis, J. Hirschhorn, R. Loos, K. Mohlke, I. Barroso, M. McCarthy. Wrote the paper: C. Lindgren, I. Heid, J. Randall., C. Lamina, V. Steinthorsdottir., L. Qi, E. Speliotes, G. Thorleifsson, C. Willer, C. Van Duijn, M. Boehnke, U.Thorsteinsdottir, G. Abecasis, J. Hirschhorn, R. Loos, K. Stefansson, K. Mohlke, I. Barroso, M. McCarthy. Directed the project: G. Abecasis, J. Hirschhorn, R. Loos, K. Stefansson, K. Mohlke, I. Barroso, M. McCarthy.

            ¶ A full list of members is provided in Text S1.

            Contributors
            Role: Editor
            Journal
            PLoS Genet
            plos
            plosgen
            PLoS Genetics
            Public Library of Science (San Francisco, USA )
            1553-7390
            1553-7404
            June 2009
            June 2009
            26 June 2009
            : 5
            : 6
            2695778
            19557161
            09-PLGE-RA-0273R2
            10.1371/journal.pgen.1000508
            (Editor)
            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.
            Counts
            Pages: 13
            Categories
            Research Article
            Diabetes and Endocrinology
            Diabetes and Endocrinology/Obesity
            Diabetes and Endocrinology/Type 2 Diabetes
            Genetics and Genomics
            Genetics and Genomics/Complex Traits

            Genetics

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