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Am J Clin Nutr. 2019 Feb 1;109(2):276-287. doi: 10.1093/ajcn/nqy272.

Disentangling the genetics of lean mass.

Karasik D1,2, Zillikens MC3,4, Hsu YH1,5,6, Aghdassi A7, Akesson K8,9, Amin N10, Barroso I11,12,13, Bennett DA14, Bertram L15, Bochud M16, Borecki IB17,18, Broer L3,10, Buchman AS14, Byberg L19, Campbell H20, Campos-Obando N3, Cauley JA21, Cawthon PM22, Chambers JC23,24,25,26, Chen Z27, Cho NH28, Choi HJ29,30,31, Chou WC1,32, Cummings SR22, de Groot LCPGM33, De Jager PL34,35, Demuth I36,37, Diatchenko L38,39, Econs MJ40, Eiriksdottir G41, Enneman AW3, Eriksson J42, Eriksson JG43,44,45,46, Estrada K3,10,47, Evans DS22, Feitosa MF17, Fu M48, Gieger C49,50,51, Grallert H49,50,52,53,54, Gudnason V41,55, Lenore LJ56, Hayward C57, Hofman A3,4, Homuth G58, Huffman KM59, Husted LB60, Illig T49,61, Ingelsson E62, Ittermann T63, Jansson JO64, Johnson T16,65,66, Biffar R67, Jordan JM68, Jula A43, Karlsson M8,9, Khaw KT69, Kilpeläinen TO70,71,72, Klopp N49,73, Kloth JSL3, Koller DL40, Kooner JS23,25,74, Kraus WE75, Kritchevsky S76, Kutalik Z16,66, Kuulasmaa T77, Kuusisto J77, Laakso M77, Lahti J78, Lang T79, Langdahl BL60, Lerch MM7, Lewis JR80,81, Lill C82, Lind L83, Lindgren C84, Liu Y85, Livshits G86,87, Ljunggren Ö83, Loos RJF72,88,89,90, Lorentzon M91, Luan J72, Luben RN71, Malkin I86, McGuigan FE8, Medina-Gomez C3,10, Meitinger T92,93, Melhus H83, Mellström D42, Michaëlsson K19, Mitchell BD48,94, Morris AP84,95, Mosekilde L60, Nethander M42, Newman AB21, O'Connell JR48, Oostra BA96,97, Orwoll ES98, Palotie A99,100, Peacock M40, Perola M43,101,102, Peters A49,50, Prince RL80,103, Psaty BM104,105, Räikkönen K106, Ralston SH107, Ripatti S11,99,108, Rivadeneira F3,4,10, Robbins JA109, Rotter JI110, Rudan I21, Salomaa V43, Satterfield S111, Schipf S63, Shin CS29, Smith AV41,55, Smith SB112, Soranzo N11, Spector TD87, Stancáková A77, Stefansson K55,113, Steinhagen-Thiessen E36, Stolk L3,4, Streeten EA48,94, Styrkarsdottir U113, Swart KMA114, Thompson P115, Thomson CA27, Thorleifsson G113, Thorsteinsdottir U55,113, Tikkanen E43,99, Tranah GJ22, Uitterlinden AG3,4,10, van Duijn CM10,97, van Schoor NM114, Vandenput L42, Vollenweider P116, Völzke H63, Wactawski-Wende J117, Walker M118, J Wareham N70, Waterworth D119, Weedon MN120, Wichmann HE50,121,122, Widen E99, Williams FMK87, Wilson JF20, Wright NC123, Yerges-Armstrong LM48,119, Yu L14, Zhang W23,25, Zhao JH70, Zhou Y124, Nielson CM98, Harris TB56, Demissie S124, Kiel DP1,5, Ohlsson C42.

Author information

1
Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA.
2
Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
3
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
4
Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.
5
Department of Medicine, Harvard Medical School, Boston, MA.
6
Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA.
7
Department of Medicine A, University of Greifswald, Greifswald, Germany.
8
Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
9
Department of Orthopedics, Skåne University Hospital, Malmö, Sweden.
10
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
11
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
12
NIHR Cambridge Biomedical Research Centre.
13
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
14
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.
15
Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
16
University Institute for Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
17
Division of Statistical Genomics, Department of Genetics.
18
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO.
19
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
20
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, United Kingdom.
21
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
22
California Pacific Medical Center Research Institute, San Francisco, CA.
23
Cardiology, Ealing Hospital NHS Trust, London, United Kingdom.
24
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
25
Imperial College Healthcare NHS Trust, London, United Kingdom.
26
NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, United Kingdom.
27
Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ.
28
Department of Preventive Medicine, Ajou University School of Medicine, Youngtong-Gu, Suwon, Korea.
29
Department of Internal Medicine.
30
Department of Anatomy and Cell Biology, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea.
31
Wide River Institute of Immunology, Seoul National University, Hongcheon, Korea.
32
Broad Institute, Cambridge, MA.
33
Division of Human Nutrition, Wageningen University, AFSG, Wageningen, The Netherlands.
34
Center for Translational and Computational Neuroimmunology, Neurology, Columbia University Medical Center, New York, NY.
35
Cell Circuits Program, Broad Institute, Cambridge, MA.
36
Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
37
Berlin Institute of Health, Berlin, Germany.
38
Regional Center for Neurosensory Disorders, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC.
39
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
40
Department of Medicine and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
41
Icelandic Heart Association Holtasmari, Kopavogur, Iceland.
42
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
43
National Institute for Health and Welfare, Helsinki, Finland.
44
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
45
Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.
46
Folkhalsan Research Centre, Helsinki, Finland.
47
Translational Biology, Biogen, Cambridge, MA.
48
Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
49
Research Unit of Molecular Epidemiology.
50
Institute of Epidemiology II.
51
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
52
CCG Type 2 Diabetes, Helmholtz Zentrum München, Neuherberg, Germany.
53
German Center for Diabetes Research, Neuherberg, Germany.
54
CCG Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Neuherberg, Germany.
55
University of Iceland, Faculty of Medicine, Reykjavik, Iceland.
56
Laboratory of Epidemiology and Population Sciences, Intramural Research Program, NIA, Bethesda, MD.
57
MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
58
Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
59
Duke Molecular Physiology Institute and Division of Rheumatology, Department of Medicine, Duke University School of Medicine, Durham, NC.
60
Aarhus University Hospital, Endocrinology and Internal Medicine, Aarhus, Denmark.
61
Department of Human Genetics, Hannover Medical School, Hanover, Germany.
62
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA.
63
Institute for Community Medicine, University of Greifswald, Greifswald, Germany.
64
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
65
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
66
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
67
Centre of Oral Health, Department of Prosthetic Dentistry, Gerodontology and Biomaterials, University of Greifswald, Greifswald, Germany.
68
Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
69
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
70
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
71
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
72
Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY.
73
Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
74
Faculty of Medicine, National Heart & Lung Institute, Cardiovascular Science, Hammersmith Campus, Hammersmith Hospital, Imperial College London, United Kingdom.
75
Duke Molecular Physiology Institute and Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC.
76
Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, NC.
77
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
78
Helsinki Collegium Advanced Studies, University of Helsinki, Helsinki, Finland.
79
Department of Radiology and Biomedical Imaging, and School of Dentistry, UC San Francisco, San Francisco, CA.
80
School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
81
Centre for Kidney Research, Children's Hospital at Westmead, School of Public Health, Sydney Medical School, The University of Sydney, Sydney, Australia.
82
Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
83
Department. of Medical Sciences, Uppsala University, Uppsala, Sweden.
84
Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, United Kingdom.
85
Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC.
86
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
87
Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Campus, London, United Kingdom.
88
The Charles Bronfman Institute of Personalized Medicine.
89
Institute of Child Health and Development.
90
The Genetics of Obesity and Related Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY.
91
Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
92
Institute of Human Genetics, MRI, Technische Universität München, Munich, Germany.
93
Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
94
Geriatric Research and Education Clinical Center-Veterans Administration Medical Center, Baltimore, MD.
95
Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
96
Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
97
Centre for Medical Systems Biology & Netherlands Consortium on Healthy Aging, Leiden, The Netherlands.
98
Oregon Health & Science University, Portland, OR.
99
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
100
Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
101
University of Helsinki, Institute for Molecular Medicine, Finland and Diabetes and Obesity Research Program, Helsinki, Finland.
102
University of Tartu, Estonian Genome Center, Tartu, Estonia.
103
Department of Endocrinology and Diabetes, Sir Charles Gardiner Hospital, Perth, Australia.
104
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA.
105
Kaiser Permanente Washington Health Research Institute, Seattle, WA.
106
Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
107
Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom.
108
Hjelt Institute, University of Helsinki, Helsinki, Finland.
109
Department of Medicine, University California at Davis, Sacramento, CA.
110
Institute for Translational Genomic and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor UCLA Medical Center, Torrance, CA.
111
Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN.
112
Center for Translational Pain Medicine, Department of Anesthesiology, Duke University, Durham, NC.
113
deCODE Genetics, Reykjavik, Iceland.
114
Department of Epidemiology and Biostatistics, and the EMGO+ Institute; VU University Medical Center, Amsterdam, The Netherlands.
115
Department of Pathology, Stony Brook University, Stony Brook, NY.
116
Department of Medicine, Internal Medicine, Lausanne University Hospital and Faculty of Biology and Medicine, Lausanne, Switzerland.
117
Department of Epidemiology and Environmental Health, University at Buffalo, SUNY, Buffalo, NY.
118
Institute of Cellular Medicine (Diabetes), The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
119
Genetics, GlaxoSmithKline, King of Prussia, PA.
120
Genetics of Complex Traits, Royal Devon & Exeter Hospital, University of Exeter Medical School, Exeter, United Kingdom.
121
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Neuherberg/Munich, Germany.
122
Institute of Medical Statistics and Epidemiology, Technical University, Munich, Germany.
123
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
124
Department of Biostatistics, Boston University School of Public Health, Boston, MA.

Abstract

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.

PMID:
30721968
PMCID:
PMC6500901
[Available on 2020-02-01]
DOI:
10.1093/ajcn/nqy272

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