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Nat Commun. 2016 Feb 1;7:10494. doi: 10.1038/ncomms10494.

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Kilpeläinen TO1,2,3, Carli JF4, Skowronski AA5, Sun Q6,7, Kriebel J8,9,10, Feitosa MF11, Hedman ÅK12,13,14, Drong AW14, Hayes JE15,16, Zhao J2, Pers TH1,17,18,19,20, Schick U3, Grarup N1, Kutalik Z21,22, Trompet S23,24, Mangino M25,26, Kristiansson K27,28, Beekman M29, Lyytikäinen LP30,31, Eriksson J32, Henneman P33,34, Lahti J35,36, Tanaka T37, Luan J2, Del Greco M F38, Pasko D39, Renström F40,41, Willems SM42, Mahajan A14, Rose LM43, Guo X44, Liu Y45, Kleber ME46, Pérusse L47,48, Gaunt T49, Ahluwalia TS1,50,51, Ju Sung Y52,53, Ramos YF29, Amin N54, Amuzu A55, Barroso I56,57,58, Bellis C59,60,61, Blangero J61, Buckley BM62, Böhringer S29, I Chen YD44, de Craen AJ24, Crosslin DR63,64, Dale CE55, Dastani Z65, Day FR2, Deelen J29, Delgado GE46, Demirkan A54,33, Finucane FM2, Ford I66, Garcia ME67, Gieger C8,9,68, Gustafsson S12,13, Hallmans G41, Hankinson SE6,69,70, Havulinna AS27, Herder C10,71, Hernandez D72, Hicks AA38, Hunter DJ73, Illig T8,74,75, Ingelsson E12,13,76, Ioan-Facsinay A77, Jansson JO78, Jenny NS79, Jørgensen ME51, Jørgensen T80,81,82, Karlsson M83, Koenig W84,85,86, Kraft P87, Kwekkeboom J77, Laatikainen T27,88,89, Ladwig KH9,90, LeDuc CA91, Lowe G92, Lu Y3, Marques-Vidal P93, Meisinger C9,10, Menni C25, Morris AP14,94, Myers RH95, Männistö S27, Nalls MA72, Paternoster L49, Peters A9,10,86, Pradhan AD43,96, Rankinen T97, Rasmussen-Torvik LJ98, Rathmann W99, Rice TK52,53, Brent Richards J25,100, Ridker PM43,96, Sattar N101, Savage DB58, Söderberg S102, Timpson NJ49, Vandenput L32, van Heemst D24, Uh HW29, Vohl MC48,103, Walker M104, Wichmann HE105,106,107, Widén E28, Wood AR39, Yao J44, Zeller T108,109, Zhang Y91, Meulenbelt I29, Kloppenburg M77,110, Astrup A111, Sørensen TI1,49,112, Sarzynski MA97, Rao DC11,52,53, Jousilahti P27, Vartiainen E27, Hofman A42, Rivadeneira F42,113, Uitterlinden AG42,113, Kajantie E27,114,115, Osmond C116, Palotie A28,56,117, Eriksson JG27,36,118, Heliövaara M27, Knekt PB27, Koskinen S27, Jula A27, Perola M27,28,119, Huupponen RK120,121, Viikari JS122,123, Kähönen M124,125, Lehtimäki T30,31, Raitakari OT126,127, Mellström D32, Lorentzon M32, Casas JP128, Bandinelli S129, März W46,130,131, Isaacs A54, van Dijk KW33, van Duijn CM54,132, Harris TB133, Bouchard C97, Allison MA134, Chasman DI43,96, Ohlsson C32, Lind L135, Scott RA2, Langenberg C2, Wareham NJ2, Ferrucci L37, Frayling TM39, Pramstaller PP38,136,137, Borecki IB11, Waterworth DM138, Bergmann S22,139, Waeber G93, Vollenweider P93, Vestergaard H1,51, Hansen T1,140, Pedersen O1, Hu FB73, Eline Slagboom P29, Grallert H8,9,10, Spector TD25, Jukema JW23,141,142, Klein RJ16, Schadt EE16, Franks PW7,40,143, Lindgren CM14,144,145, Leibel RL91, Loos RJ2,3,146.

Author information

1
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, DIKU Building, Copenhagen 2100, Denmark.
2
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.
3
Genetics of Obesity and Related Metabolic Traits Program, Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
4
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
5
Institute of Human Nutrition, Columbia University, New York, New York 10032, USA.
6
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachussetts 02115, USA.
7
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachussetts 02115, USA.
8
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
9
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
10
German Center for Diabetes Research (DZD), München-Neuherberg 85764, Germany.
11
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
12
Science for Life Laboratory, Uppsala University, Uppsala 750 85, Sweden.
13
Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.
14
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
15
Cell and Developmental Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA.
16
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
17
Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachussetts 02115, USA.
18
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 2142, USA.
19
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
20
Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark.
21
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne 1010, Switzerland.
22
Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
23
Department of Cardiology, Leiden University Medical Center, Leiden 2333, The Netherlands.
24
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2333, The Netherlands.
25
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
26
National Institute for Health Research Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London SE1 9RT, UK.
27
Department of Health, National Institute for Health and Welfare, Helsinki FI-00271, Finland.
28
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki FI-00290, Finland.
29
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
30
Department of Clinical Chemistry, Fimlab Laboratories, Tampere FI-33101, Finland.
31
Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere FI-33014, Finland.
32
Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 413 45, Sweden.
33
Department of Human Genetics, Leiden University Medical Center, Leiden 2333, The Netherlands.
34
Department of Clinical Genetics, Amsterdam Medical Center, Amsterdam 1081 HV, The Netherlands.
35
Institute of Behavioural Sciences, University of Helsinki, Helsinki FI-00014, Finland.
36
Folkhälsan Research Center, Helsinki FI-00290, Finland.
37
Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland 21225, USA.
38
Center for Biomedicine, European Academy Bozen/Bolzano (EURAC) - Affiliated Institute of the University of Lübeck, Bolzano 39100, Italy.
39
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
40
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö 20502, Sweden.
41
Department of Biobank Research, Umeå University, Umeå 90187, Sweden.
42
Department of Epidemiology, Erasmus MC, Rotterdam 3015 GE, The Netherlands.
43
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachussetts 02215, USA.
44
Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Institute for Translational Genomics and Population Sciences, Torrance, California 90502, USA.
45
Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
46
Medical Faculty Mannheim, Vth Department of Medicine, Heidelberg University, Mannheim 68167, Germany.
47
Department of Kinesiology, Laval University, Quebec City, Quebec, Canada G1V 0A6.
48
Institute of Nutrition and Functional Foods, Quebec City, Quebec, Canada G1V 0A6.
49
MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol BS82BN, UK.
50
COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Allé, Copenhagen DK-2820, Denmark.
51
Steno Diabetes Center, Gentofte DK-2820, Denmark.
52
Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
53
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
54
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam 3015 GE, The Netherlands.
55
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
56
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
57
NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
58
The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
59
Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research of Singapore, Singapore 138672, Singapore.
60
Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4001, Australia.
61
Texas Biomedical Research Institute, San Antonio, Texas 78245, USA.
62
Department of Pharmacology and Therapeutics, University College Cork, Cork T12 YT57, Ireland.
63
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
64
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
65
Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 0G4.
66
Robertson Center for Biostatistics, University of Glasgow, Glasgow G12 8QQ, UK.
67
National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 2089, USA.
68
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
69
Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts 01003, USA.
70
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
71
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany.
72
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892, USA.
73
Department of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
74
Hannover Unified Biobank, Hannover Medical School, Hannover 30625, Germany.
75
Institute for Human Genetics, Hannover Medical School, Hannover 30625, Germany.
76
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
77
Department of Rheumatology, Leiden University Medical Center, Leiden 2333, The Netherlands.
78
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden.
79
Laboratory for Clinical Biochemistry Research, Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Colchester, Vermont 05405, USA.
80
Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup 2600, Denmark.
81
Faculty of Medicine, University of Aalborg, Aalborg 9100, Denmark.
82
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
83
Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences and Orthopaedic Surgery, Lund University, Skåne University Hospital, Malmö 21428, Sweden.
84
Department of Internal Medicine II - Cardiology, University of Ulm, Ulm 89081, Germany.
85
Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany.
86
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich 80539, Germany.
87
Department of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachussetts 02115, USA.
88
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio FI-70211, Finland.
89
Hospital District of North Karelia, Joensuu FI-80210, Finland.
90
Department of Psychosomatic Medicine and Psychotherapy, Klinikum Rechts der Isar, Technische Universität München, Munich 81675, Germany.
91
Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, New York 10029, USA.
92
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
93
Department of Internal Medicine, Lausanne University Hospital, Lausanne 1011, Switzerland.
94
Department of Biostatistics, University of Liverpool, Liverpool L69 3GA, UK.
95
Department of Neurology, Boston University School of Medicine, Boston, Massachussetts 02118, USA.
96
Harvard Medical School, Boston, Massachussetts 02115, USA.
97
Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Los Angeles 70808, USA.
98
Preventive Medicine, Northwestern Feinberg School of Medicine, Chicago, Illinois 60611, USA.
99
Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany.
100
Department of Medicine, Human Genetics and Epidemiology, McGill University, Montreal, Quebec, Canada H3A 0G4.
101
Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre, Glasgow G12 8QQ, UK.
102
Department of Public Health and Clinical Medicine, Cardiology and Heart Centre, Umeå University, Umeå 90187, Sweden.
103
School of Nutrition, Laval University, Quebec City, Quebec, Canada G1V 0A6.
104
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
105
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität and Klinikum Grosshadern, Munich 80336, Germany.
106
Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
107
Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich 81675, Germany.
108
German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg/Kiel/Lübeck, Hamburg 20246, Germany.
109
Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg 20246, Germany.
110
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333, The Netherlands.
111
Faculty of Science, Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen 1165, Denmark.
112
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen 2000, Denmark.
113
Department of Internal Medicine, Erasmus MC, Rotterdam 3015 GE, The Netherlands.
114
Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki FI-00014, Finland.
115
Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Central Hospital and University of Oulu, Oulu 90220, Finland.
116
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
117
Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
118
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki FI-00014, Finland.
119
University of Tartu, Estonian Genome Centre, Tartu 51010, Estonia.
120
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku FI-20520, Finland.
121
Unit of Clinical Pharmacology, Turku University Hospital, Turku FI-20520, Finland.
122
Division of Medicine, Turku University Hospital, Turku FI-20520, Finland.
123
Department of Medicine, University of Turku, Turku FI-20520, Finland.
124
Department of Clinical Physiology, Tampere University Hospital, Tampere FI-33521, Finland.
125
Department of Clinical Physiology, University of Tampere School of Medicine, Tampere FI-33014, Finland.
126
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku FI-2051, Finland.
127
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku FI-20520, Finland.
128
Farr Institute of Health Informatics, University College London, London NW1 2DA, UK.
129
Geriatric Unit, Azienda Sanitaria Firenze, Florence 50122, Italy.
130
Synlab Academy, Synlab Services LLC, Mannheim 68161, Germany.
131
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8010, Austria.
132
Center of Medical Systems Biology, Leiden 2300 RC, The Netherlands.
133
Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, Maryland 20892, USA.
134
Family and Preventive Medicine, University of California-San Diego, La Jolla, California 92161, USA.
135
Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 75185, Sweden.
136
Department of Neurology, General Central Hospital, Bolzano 39100, Italy.
137
Department of Neurology, University of Lübeck, Lübeck 23562, Germany.
138
GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
139
Department of Medical Genetics, University of Lausanne, Lausanne 1015, Switzerland.
140
Faculty of Health Sciences, University of Southern Denmark, Odense 5230, Denmark.
141
Interuniversity Cardiology Institute of the Netherlands, Utrecht 3511 EP, The Netherlands.
142
Durrer Center for Cardiogenetic Research, Amsterdam 1105 AZ, The Netherlands.
143
Department of Public Health and Clinical Medicine, Umeå University, Umeå 90187, Sweden.
144
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachussetts 02142, USA.
145
The Big Data Institute, University of Oxford, Oxford OX1 2JD, UK.
146
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

PMID:
26833098
PMCID:
PMC4740377
DOI:
10.1038/ncomms10494
[Indexed for MEDLINE]
Free PMC Article

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