Karasik DHebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA.
Zillikens MCDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Hsu YHHebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA.
Aghdassi ADepartment of Medicine A, University of Greifswald, Greifswald, Germany.
Akesson KDepartment of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Amin NDepartment of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
Barroso IWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
Bennett DARush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.
Bertram LLübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
Bochud MUniversity Institute for Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
Borecki IBDivision of Statistical Genomics, Department of Genetics.
Broer LDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Buchman ASRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.
Byberg LDepartment of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Campbell HCentre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, United Kingdom.
Campos-Obando NDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Cauley JADepartment of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
Cawthon PMCalifornia Pacific Medical Center Research Institute, San Francisco, CA.
Chambers JCCardiology, Ealing Hospital NHS Trust, London, United Kingdom.
Chen ZMel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ.
Cho NHDepartment of Preventive Medicine, Ajou University School of Medicine, Youngtong-Gu, Suwon, Korea.
Chou WCHebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA.
Cummings SRCalifornia Pacific Medical Center Research Institute, San Francisco, CA.
de Groot LCPGMDivision of Human Nutrition, Wageningen University, AFSG, Wageningen, The Netherlands.
De Jager PLCenter for Translational and Computational Neuroimmunology, Neurology, Columbia University Medical Center, New York, NY.
Demuth ICharité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Diatchenko LRegional Center for Neurosensory Disorders, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Econs MJDepartment of Medicine and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
Eiriksdottir GIcelandic Heart Association Holtasmari, Kopavogur, Iceland.
Enneman AWDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Eriksson JDepartment of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Eriksson JGNational Institute for Health and Welfare, Helsinki, Finland.
Estrada KDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Evans DSCalifornia Pacific Medical Center Research Institute, San Francisco, CA.
Feitosa MFDivision of Statistical Genomics, Department of Genetics.
Fu MProgram in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
Kloth JSLDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Koller DLDepartment of Medicine and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
Kooner JSCardiology, Ealing Hospital NHS Trust, London, United Kingdom.
Kraus WEDuke Molecular Physiology Institute and Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC.
Kritchevsky SSticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, NC.
Kutalik ZUniversity Institute for Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
Kuulasmaa TDepartment of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Kuusisto JDepartment of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Laakso MDepartment of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Lahti JHelsinki Collegium Advanced Studies, University of Helsinki, Helsinki, Finland.
Lang TDepartment of Radiology and Biomedical Imaging, and School of Dentistry, UC San Francisco, San Francisco, CA.
Langdahl BLAarhus University Hospital, Endocrinology and Internal Medicine, Aarhus, Denmark.
Lerch MMDepartment of Medicine A, University of Greifswald, Greifswald, Germany.
Lewis JRSchool of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
Lill CInstitute of Neurogenetics, University of Luebeck, Luebeck, Germany.
Lind LDepartment. of Medical Sciences, Uppsala University, Uppsala, Sweden.
Lindgren CWellcome Trust Centre for Human Genetics, Oxford University, Oxford, United Kingdom.
Liu YDepartment of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC.
Livshits GDepartment of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Ljunggren ÖDepartment. of Medical Sciences, Uppsala University, Uppsala, Sweden.
Loos RJFDepartment of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY.
Lorentzon MDepartment of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Luan JDepartment of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY.
Luben RNNovo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Malkin IDepartment of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
McGuigan FEDepartment of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Medina-Gomez CDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Meitinger TInstitute of Human Genetics, MRI, Technische Universität München, Munich, Germany.
Melhus HDepartment. of Medical Sciences, Uppsala University, Uppsala, Sweden.
Mellström DDepartment of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Michaëlsson KDepartment of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Mitchell BDProgram in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
Morris APWellcome Trust Centre for Human Genetics, Oxford University, Oxford, United Kingdom.
Mosekilde LAarhus University Hospital, Endocrinology and Internal Medicine, Aarhus, Denmark.
Nethander MDepartment of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Newman ABDepartment of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
O'Connell JRProgram in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
Oostra BADepartment of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
Orwoll ESOregon Health & Science University, Portland, OR.
Palotie AInstitute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Peacock MDepartment of Medicine and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
Perola MNational Institute for Health and Welfare, Helsinki, Finland.
Prince RLSchool of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
Psaty BMCardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA.
Räikkönen KDepartment of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
Ralston SHMolecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom.
Ripatti SWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
Rivadeneira FDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Robbins JADepartment of Medicine, University California at Davis, Sacramento, CA.
Rotter JIInstitute for Translational Genomic and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor UCLA Medical Center, Torrance, CA.
Rudan IDepartment of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
Salomaa VNational Institute for Health and Welfare, Helsinki, Finland.
Satterfield SDepartment of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN.
Schipf SInstitute for Community Medicine, University of Greifswald, Greifswald, Germany.
Smith AVIcelandic Heart Association Holtasmari, Kopavogur, Iceland.
Smith SBCenter for Translational Pain Medicine, Department of Anesthesiology, Duke University, Durham, NC.
Soranzo NWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
Spector TDDepartment of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Campus, London, United Kingdom.
Stancáková ADepartment of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Stefansson KUniversity of Iceland, Faculty of Medicine, Reykjavik, Iceland.
Steinhagen-Thiessen ECharité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Stolk LDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Streeten EAProgram in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
Thorsteinsdottir UUniversity of Iceland, Faculty of Medicine, Reykjavik, Iceland.
Tikkanen ENational Institute for Health and Welfare, Helsinki, Finland.
Tranah GJCalifornia Pacific Medical Center Research Institute, San Francisco, CA.
Uitterlinden AGDepartment of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
van Duijn CMDepartment of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
van Schoor NMDepartment of Epidemiology and Biostatistics, and the EMGO+ Institute; VU University Medical Center, Amsterdam, The Netherlands.
Vandenput LDepartment of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Vollenweider PDepartment of Medicine, Internal Medicine, Lausanne University Hospital and Faculty of Biology and Medicine, Lausanne, Switzerland.
Völzke HInstitute for Community Medicine, University of Greifswald, Greifswald, Germany.
Wactawski-Wende JDepartment of Epidemiology and Environmental Health, University at Buffalo, SUNY, Buffalo, NY.
Walker MInstitute of Cellular Medicine (Diabetes), The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
J Wareham NMRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Waterworth DGenetics, GlaxoSmithKline, King of Prussia, PA.
Weedon MNGenetics of Complex Traits, Royal Devon & Exeter Hospital, University of Exeter Medical School, Exeter, United Kingdom.
Widen EInstitute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Williams FMKDepartment of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Campus, London, United Kingdom.
Wilson JFCentre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, United Kingdom.
Wright NCDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
Yerges-Armstrong LMProgram in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
Yu LRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.
Zhang WCardiology, Ealing Hospital NHS Trust, London, United Kingdom.
Zhao JHMRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Zhou YDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Nielson CMOregon Health & Science University, Portland, OR.
Harris TBLaboratory of Epidemiology and Population Sciences, Intramural Research Program, NIA, Bethesda, MD.
Demissie SDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Kiel DPHebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA.
Ohlsson CDepartment of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
English
Background Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.
Objectives To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.
Methods We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).
Results Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.
Conclusions In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.