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Nat Commun. 2017 Jul 19;8(1):80. doi: 10.1038/s41467-017-00031-7.

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Zillikens MC1,2, Demissie S3, Hsu YH4,5,6, Yerges-Armstrong LM7, Chou WC4,5,8, Stolk L1,2, Livshits G9,10, Broer L11, Johnson T12,13,14, Koller DL15, Kutalik Z12,13,14, Luan J16, Malkin I9, Ried JS17, Smith AV18,19, Thorleifsson G20, Vandenput L21, Hua Zhao J16, Zhang W22,23, Aghdassi A24, Åkesson K25,26, Amin N11, Baier LJ27, Barroso I28,29,30, Bennett DA31, Bertram L32,33, Biffar R34, Bochud M14, Boehnke M35, Borecki IB36,37, Buchman AS31, Byberg L38, Campbell H39, Campos Obanda N1, Cauley JA40, Cawthon PM41, Cederberg H42, Chen Z43, Cho NH44, Jin Choi H45,46, Claussnitzer M4,5,8,47,48,49, Collins F50, Cummings SR41, De Jager PL5,51,52, Demuth I53,54, Dhonukshe-Rutten RAM55, Diatchenko L56,57, Eiriksdottir G18, Enneman AW1, Erdos M50, Eriksson JG58,59,60,61,62, Eriksson J21, Estrada K1,11, Evans DS41, Feitosa MF36, Fu M7, Garcia M63, Gieger C17,64,65, Girke T66,67, Glazer NL68, Grallert H17,64,67,69,70,71, Grewal J23,72, Han BG73, Hanson RL27, Hayward C74, Hofman A2,11, Hoffman EP75, Homuth G76, Hsueh WC27, Hubal MJ77,78, Hubbard A79, Huffman KM80, Husted LB81, Illig T64,82,83, Ingelsson E84,85, Ittermann T86, Jansson JO87, Jordan JM88, Jula A62, Karlsson M89, Khaw KT90, Kilpeläinen TO16,91,92, Klopp N64,83, Kloth JSL1, Koistinen HA93,94,95,96, Kraus WE97, Kritchevsky S98, Kuulasmaa T42, Kuusisto J42, Laakso M42, Lahti J99, Lang T100, Langdahl BL81, Launer LJ63, Lee JY73, Lerch MM24, Lewis JR101,102, Lind L84, Lindgren C103, Liu Y104, Liu T105,106, Liu Y88, Ljunggren Ö84, Lorentzon M21, Luben RN90, Maixner W57, McGuigan FE25, Medina-Gomez C1,11, Meitinger T48,107, Melhus H84, Mellström D21, Melov S108,109, Michaëlsson K38, Mitchell BD7,110, Morris AP103,111, Mosekilde L81, Newman A112, Nielson CM113, O'Connell JR7, Oostra BA114,115, Orwoll ES113, Palotie A116,117, Parker SCJ118, Peacock M119, Perola M62,116,120,121, Peters A17,64, Polasek O122, Prince RL101,123, Räikkönen K99, Ralston SH124, Ripatti S116,125,28, Robbins JA126, Rotter JI127, Rudan I39, Salomaa V62, Satterfield S128, Schadt EE129, Schipf S86, Scott L35, Sehmi J23,72, Shen J113, Soo Shin C45, Sigurdsson G19,130, Smith S131, Soranzo N28, Stančáková A42, Steinhagen-Thiessen E53, Streeten EA7,132, Styrkarsdottir U20, Swart KMA133, Tan ST23,72, Tarnopolsky MA134, Thompson P135, Thomson CA43, Thorsteinsdottir U19,20, Tikkanen E62,116,124, Tranah GJ41, Tuomilehto J61,136,137,138, van Schoor NM133, Verma A23, Vollenweider P139, Völzke H86, Wactawski-Wende J140, Walker M141, Weedon MN142, Welch R35, Wichmann HE17,143,144, Widen E116, Williams FMK10, Wilson JF39,74, Wright NC145, Xie W142, Yu L31, Zhou Y3, Chambers JC22,23,146,147, Döring A17,148, van Duijn CM11,115, Econs MJ149, Gudnason V18,19, Kooner JS23,72,147, Psaty BM150,151, Spector TD10, Stefansson K19,20, Rivadeneira F1,2,11, Uitterlinden AG1,2,11, Wareham NJ16, Ossowski V27, Waterworth D152, Loos RJF16,153,154,155,156, Karasik D4,5,157, Harris TB63, Ohlsson C21, Kiel DP158,159,160.

Author information

1
Department of Internal Medicine, Erasmus MC, Rotterdam, 3000, The Netherlands.
2
Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, 2593, The Netherlands.
3
Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
4
Hebrew SeniorLife, Institute for Aging Research, Roslindale, MA, 02131, USA.
5
Harvard Medical School, Boston, MA, 02115, USA.
6
Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, 02115, USA.
7
Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
8
Broad Institute, Cambridge, MA, 02142, USA.
9
Sackler Faculty of Medicine, Department of Anatomy and Anthropology, Tel Aviv University, Tel Aviv, 6997801, Israel.
10
Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Campus, London, WC2R 2LS, UK.
11
Department of Epidemiology, Erasmus MC, Rotterdam, 3000, The Netherlands.
12
Department of Medical Genetics, University of Lausanne, Lausanne, 1011, Switzerland.
13
Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland.
14
Centre Hospitalier Universitaire (CHUV), University Institute for Social and Preventive Medicine, Lausanne, 1010, Switzerland.
15
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
16
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, CB2 OQQ, UK.
17
Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany.
18
Icelandic Heart Association, Kopavogur, 201, Iceland.
19
Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
20
deCODE Genetics, Reykjavik, 101, Iceland.
21
Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SE-405 30, Sweden.
22
Department Epidemiology and Biostatistics, School of Public Health, Imperial College, London, SW7 2AZ, UK.
23
Cardiology Department, Ealing Hospital NHS Trust, Middlesex, UB1 3HW, UK.
24
Department of Medicine A, University of Greifswald, Greifswald, 17489, Germany.
25
Department of Clinical Sciences, Lund University, Malmö, 22362, Sweden.
26
Department of Orthopedics, Skåne University Hospital, Malmö, S-205 02, Sweden.
27
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Phoenix, AZ, 85014, USA.
28
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
29
NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 OQQ, UK.
30
Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, CB2 OQQ, UK.
31
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 60612, USA.
32
Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Experimental & Integrative Genomics, University of Lübeck, Lübeck, 23562, Germany.
33
School of Public Health, Faculty of Medicine, Imperial College London, London, W6 8RP, UK.
34
Centre of Oral Health, Department of Prosthetic Dentistry, Gerodontology and Biomaterials, University of Greifswald, Greifswald, 17489, Germany.
35
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
36
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, USA.
37
Division of Biostatistics, Washington University School of Medicine, St Louis, MO, 63110, USA.
38
Department of Surgical Sciences, Uppsala University, Uppsala, 75185, Sweden.
39
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, EH8 9AG, UK.
40
Department of Epidemiology Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
41
California Pacific Medical Center Research Institute, San Francisco, CA, 94107, USA.
42
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, 70210, Finland.
43
Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, 85714, USA.
44
Department of Preventive Medicine, Ajou University School of Medicine, Youngtong-Gu, Suwon, 16499, Korea.
45
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.
46
Department of Internal Medicine, Chungbuk National University Hospital, Cheongju Si, Korea.
47
Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, 02139, USA.
48
Institute of Human Genetics, MRI, Technische Universität München, Munich, 81675, Germany.
49
Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
50
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
51
Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
52
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.
53
Lipid Clinic at the Interdisciplinary Metabolism Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 13353, Germany.
54
Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, 13353, Germany.
55
Department of Human Nutrition, Wageningen University, PO Box 17, Wageningen, 6700 AA, The Netherlands.
56
Alan Edwards Centre for Research on Pain, McGill University, Montreal, H3A 0G1, Canada.
57
Regional Center for Neurosensory Disorders, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
58
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, 00014, Finland.
59
Unit of General Practice, Helsinki University Central Hospital, Helsinki, 00014, Finland.
60
Folkhalsan Research Centre, Helsinki, 00250, Finland.
61
Vasa Central Hospital, Vasa, 65130, Finland.
62
National Institute for Health and Welfare, Helsinki, 00271, Finland.
63
Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute for Aging, Bethesda, MD, 20892, USA.
64
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany.
65
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany.
66
Institute for Integrative Genome Biology, University of California, Riverside, CA, 92521, USA.
67
Department of Botany and Plant Sciences, University of California, Riverside, CA, 92521, USA.
68
Departments of Medicine and Epidemiology, Boston University School of Medicine and Public Health, Boston, MA, 02118, USA.
69
German Center for Diabetes Research (DZD), Neuherberg, Germany.
70
CCG Type 2 Diabetes, Helmholtz Zentrum München, Neuherberg, 85764, Germany.
71
CCG Nutrigenomics and Type 2 Diabetes. Helmholtz Zentrum München, Neuherberg, 85764, Germany.
72
National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.
73
Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, 28159, Korea.
74
MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, Scotland, EH4 2XU, UK.
75
Department of Pharmaceutical Sciences, SUNY Binghamton, Binghamton, NY, 13902, USA.
76
Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, 17487, Germany.
77
Department of Exercise and Nutrition Sciences, George Washington University, Washington, DC, 20052, USA.
78
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20052, USA.
79
Division of Biostatistics, School of Public Health, University of California, Berkeley, CA, 94720, USA.
80
Division of Rheumatology, Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, 27710, USA.
81
Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, DK 8000, Denmark.
82
Department of Human Genetics, Hannover Medical School, Hannover, 30625, Germany.
83
Hannover Unified Biobank, Hannover Medical School, Hannover, 30625, Germany.
84
Department of Medical Sciences, Uppsala University, Uppsala, 75185, Sweden.
85
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
86
Institute for Community Medicine, University of Greifswald, Greifswald, 17489, Germany.
87
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SE 405 30, Sweden.
88
Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27517, USA.
89
Department of Clinical Sciences and Orthopaedics, Lund University, Skåne University Hospital SUS, Malmö, 22362, Sweden.
90
Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
91
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, 2100, Denmark.
92
Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
93
Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, 00029, Finland.
94
Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, 00029, Finland.
95
Department of Health, National Institute for Health and Welfare, Helsinki, 00271, Finland.
96
Minerva Foundation Institute for Medical Research, Helsinki, 00290, Finland.
97
Division of Cardiology, Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, 27710, USA.
98
Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
99
Institute of Behavioural Sciences, University of Helsinki, Helsinki, FI00014, Finland.
100
University of California San Francisco, San Francisco, CA, 94143, USA.
101
School of Medicine and Pharmacology, University of Western Australia, Perth, 6009, Australia.
102
Centre for Kidney Research, School of Public Health, University of Sydney, Sydney, 2006, Australia.
103
Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, OX3 7BN, UK.
104
Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, 27517, USA.
105
Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany.
106
Max Planck Institute for Human Development, Berlin, 14195, Germany.
107
Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany.
108
Buck Institute for Research on Aging, Novato, CA, 94945, USA.
109
Leonard Davis School of Gerontology, University of Southern California, LA, CA, 90089, USA.
110
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, 21201, USA.
111
Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK.
112
Center for Aging and Population Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
113
Oregon Health & Science University, Portland, OR, 97239, USA.
114
Department of Clinical Genetics, Erasmus MC, Rotterdam, 300 CA, The Netherlands.
115
Centre for Medical Systems Biology and Netherlands Consortium on Healthy Aging, Leiden, RC2300, The Netherlands.
116
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00251, Finland.
117
Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, FI00014, Finland.
118
Human Genetics and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
119
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
120
Diabetes and Obesity Research Program, University of Helsinki, Helsinki, FI00014, Finland.
121
Estonian Genome Center, University of Tartu, Tartu, Estonia.
122
Faculty of Medicine, Department of Public Health, University of Split, Split, 21000, Croatia.
123
Department of Endocrinology and Diabetes, Sir Charles Gardiner Hospital, Perth, 6009, Australia.
124
Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, EH4 2XU, UK.
125
Hjelt Institute, University of Helsinki, Helsinki, Finland.
126
Department of Medicine, University of California at Davis, Sacramento, CA, 95817, USA.
127
Institute for Translational Genomic and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor UCLA Medical Center, Torrance, CA, 90502, USA.
128
Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
129
Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
130
Department of Endocrinology and Metabolism, Landspitali, The National University Hospital of Iceland, Reykjavik, 101, Iceland.
131
Center for Translational Pain Medicine, Department of Anesthiology, Duke University Medical Center, Durham, NC, 27110, USA.
132
Geriatric Research and Education Clinical Center (GRECC) - Veterans Administration Medical Center, Baltimore, MD, 21201, USA.
133
Department of Epidemiology and Biostatistics, and the EMGO Institute, VU University Medical Center, Amsterdam, BT1081, The Netherlands.
134
Department of Medicine, McMaster University Medical Center, Hamilton, ON, Canada, L8N 3Z5.
135
Department of Pathology, Stony Brook School of Medicine, Stony Brook, NY, 11794, USA.
136
Department of Neuroscience and Preventive Medicine, Danube-University Krems, Krems, 3500, Austria.
137
Diabetes Research Group, King Abdulaziz University, Jeddah, 12589, Saudi Arabia.
138
Dasman Diabetes Institute, Dasman, 15462, Kuwait.
139
Department of Medicine and Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, CH-1011, Switzerland.
140
Department of Epidemiology and Environmental Health, University at Buffalo, State University of New York, Buffalo, NY, 14214, USA.
141
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
142
Genetics of Complex Traits, University of Exeter Medical School, Exeter, EX1 2LU, UK.
143
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, 81377, Germany.
144
Institute of Medical Statistics and Epidemiology, Technical University, Munich, 81675, Germany.
145
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
146
NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, SW3 6NP, UK.
147
Imperial College Healthcare NHS Trust, London, W2 1NY, UK.
148
Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany.
149
Department of Medicine and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
150
Departments of Medicine, Epidemiology, and Health Services, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98101, USA.
151
Kaiser Permanente Washington Health Research Institute, Washington, Seattle, WA, 98101, USA.
152
Medical Genetics, GlaxoSmithKline, Philadelphia, PA, 19112, USA.
153
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
154
Institute of Child Health and Development, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
155
The Genetics of Obesity and Related Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
156
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
157
Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, 1311502, Israel.
158
Hebrew SeniorLife, Institute for Aging Research, Roslindale, MA, 02131, USA. kiel@hsl.harvard.edu.
159
Harvard Medical School, Boston, MA, 02115, USA. kiel@hsl.harvard.edu.
160
Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. kiel@hsl.harvard.edu.

Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

PMID:
28724990
PMCID:
PMC5517526
DOI:
10.1038/s41467-017-00031-7
[Indexed for MEDLINE]
Free PMC Article

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