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

Tuomas O Kilpeläinen^{1

2

3}, Jayne F Martin Carli⁴, Alicja A Skowronski⁵, Qi Sun^{6

7}, Jennifer Kriebel^{8

9

10}, Mary F Feitosa¹¹, Åsa K Hedman^{12

13

14}, Alexander W Drong¹⁴, James E Hayes^{15

16}, Jinghua Zhao², Tune H Pers^{1

17

18

19

20}, Ursula Schick³, Niels Grarup¹, Zoltán Kutalik^{21

22}, Stella Trompet^{23

24}, Massimo Mangino^{25

26}, Kati Kristiansson^{27

28}, Marian Beekman²⁹, Leo-Pekka Lyytikäinen^{30

31}, Joel Eriksson³², Peter Henneman^{33

34}, Jari Lahti^{35

36}, Toshiko Tanaka³⁷, Jian'an Luan², Fabiola Del Greco M³⁸, Dorota Pasko³⁹, Frida Renström^{40

41}, Sara M Willems⁴², Anubha Mahajan¹⁴, Lynda M Rose⁴³, Xiuqing Guo⁴⁴, Yongmei Liu⁴⁵, Marcus E Kleber⁴⁶, Louis Pérusse^{47

48}, Tom Gaunt⁴⁹, Tarunveer S Ahluwalia^{1

50

51}, Yun Ju Sung^{52

53}, Yolande F Ramos²⁹, Najaf Amin⁵⁴, Antoinette Amuzu⁵⁵, Inês Barroso^{56

57

58}, Claire Bellis^{59

60

61}, John Blangero⁶¹, Brendan M Buckley⁶², Stefan Böhringer²⁹, Yii-Der I Chen⁴⁴, Anton J N de Craen²⁴, David R Crosslin^{63

64}, Caroline E Dale⁵⁵, Zari Dastani⁶⁵, Felix R Day², Joris Deelen²⁹, Graciela E Delgado⁴⁶, Ayse Demirkan^{54

33}, Francis M Finucane², Ian Ford⁶⁶, Melissa E Garcia⁶⁷, Christian Gieger^{8

9

68}, Stefan Gustafsson^{12

13}, Göran Hallmans⁴¹, Susan E Hankinson^{6

69

70}, Aki S Havulinna²⁷, Christian Herder^{10

71}, Dena Hernandez⁷², Andrew A Hicks³⁸, David J Hunter⁷³, Thomas Illig^{8

74

75}, Erik Ingelsson^{12

13

76}, Andreea Ioan-Facsinay⁷⁷, John-Olov Jansson⁷⁸, Nancy S Jenny⁷⁹, Marit E Jørgensen⁵¹, Torben Jørgensen^{80

81

82}, Magnus Karlsson⁸³, Wolfgang Koenig^{84

85

86}, Peter Kraft⁸⁷, Joanneke Kwekkeboom⁷⁷, Tiina Laatikainen^{27

88

89}, Karl-Heinz Ladwig^{9

90}, Charles A LeDuc⁹¹, Gordon Lowe⁹², Yingchang Lu³, Pedro Marques-Vidal⁹³, Christa Meisinger^{9

10}, Cristina Menni²⁵, Andrew P Morris^{14

94}, Richard H Myers⁹⁵, Satu Männistö²⁷, Mike A Nalls⁷², Lavinia Paternoster⁴⁹, Annette Peters^{9

10

86}, Aruna D Pradhan^{43

96}, Tuomo Rankinen⁹⁷, Laura J Rasmussen-Torvik⁹⁸, Wolfgang Rathmann⁹⁹, Treva K Rice^{52

53}, J Brent Richards^{25

100}, Paul M Ridker^{43

96}, Naveed Sattar¹⁰¹, David B Savage⁵⁸, Stefan Söderberg¹⁰², Nicholas J Timpson⁴⁹, Liesbeth Vandenput³², Diana van Heemst²⁴, Hae-Won Uh²⁹, Marie-Claude Vohl^{48

103}, Mark Walker¹⁰⁴, Heinz-Erich Wichmann^{105

106

107}, Elisabeth Widén²⁸, Andrew R Wood³⁹, Jie Yao⁴⁴, Tanja Zeller^{108

109}, Yiying Zhang⁹¹, Ingrid Meulenbelt²⁹, Margreet Kloppenburg^{77

110}, Arne Astrup¹¹¹, Thorkild I A Sørensen^{1

49

112}, Mark A Sarzynski⁹⁷, D C Rao^{11

52

53}, Pekka Jousilahti²⁷, Erkki Vartiainen²⁷, Albert Hofman⁴², Fernando Rivadeneira^{42

113}, André G Uitterlinden^{42

113}, Eero Kajantie^{27

114

115}, Clive Osmond¹¹⁶, Aarno Palotie^{28

56

117}, Johan G Eriksson^{27

36

118}, Markku Heliövaara²⁷, Paul B Knekt²⁷, Seppo Koskinen²⁷, Antti Jula²⁷, Markus Perola^{27

28

119}, Risto K Huupponen^{120

121}, Jorma S Viikari^{122

123}, Mika Kähönen^{124

125}, Terho Lehtimäki^{30

31}, Olli T Raitakari^{126

127}, Dan Mellström³², Mattias Lorentzon³², Juan P Casas¹²⁸, Stefanie Bandinelli¹²⁹, Winfried März^{46

130

131}, Aaron Isaacs⁵⁴, Ko W van Dijk³³, Cornelia M van Duijn^{54

132}, Tamara B Harris¹³³, Claude Bouchard⁹⁷, Matthew A Allison¹³⁴, Daniel I Chasman^{43

96}, Claes Ohlsson³², Lars Lind¹³⁵, Robert A Scott², Claudia Langenberg², Nicholas J Wareham², Luigi Ferrucci³⁷, Timothy M Frayling³⁹, Peter P Pramstaller^{38

136

137}, Ingrid B Borecki¹¹, Dawn M Waterworth¹³⁸, Sven Bergmann^{22

139}, Gérard Waeber⁹³, Peter Vollenweider⁹³, Henrik Vestergaard^{1

51}, Torben Hansen^{1

140}, Oluf Pedersen¹, Frank B Hu⁷³, P Eline Slagboom²⁹, Harald Grallert^{8

9

10}, Tim D Spector²⁵, J W Jukema^{23

141

142}, Robert J Klein¹⁶, Erik E Schadt¹⁶, Paul W Franks^{7

40

143}, Cecilia M Lindgren^{14

144

145}, Rudolph L Leibel⁹¹, Ruth J F Loos^{2

3

146}

Affiliations

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.

PMID: 26833098
PMCID: PMC4740377
DOI: 10.1038/ncomms10494

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

Tuomas O Kilpeläinen et al. Nat Commun. 2016.

. 2016 Feb 1:7:10494.

doi: 10.1038/ncomms10494.

Authors

Affiliations

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.

PMID: 26833098
PMCID: PMC4740377
DOI: 10.1038/ncomms10494

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.

PubMed Disclaimer

Conflict of interest statement

I.B. owns stock in GlaxoSmithKline and Incyte Corporation. F.M.F. has received honoraria, speaker fees or research funding from Astra Zeneca, Merck Sharp Dohme, Eli Lilly, Novo Nordisk and Sanofi. P.W. and G.W. received grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne and the Swiss National Science Foundation (33CSCO-122661), to conduct the CoLaus study. A.A. is currently a consultant or a member of advisory board for Arena Pharmaceuticals Inc., USA; Basic Research, USA; BioCare Copenhagen, DK; Dutch Beer Knowledge Institute, NL; Gelesis, USA; Global Dairy Platform, USA; IKEA Food Scientific Health Advisory Board, SV; McCain Foods Ltd., USA; McDonald s, USA; Novo Nordisk, DK; Orexigen Therapeutics Inc., USA; S-Biotek, DK; and Weight Watchers, USA.

Figures

**Figure 1. Meta-analysis results for the leptin-associated loci.**
The bars show the additive effect of the loci in or near *LEP, GCKR, CCNL1*, *SLC32A1, COBLL1* and *FTO* on BMI-unadjusted and BMI-adjusted leptin levels in the meta-analysis of Stage 1 and Stage 2 combined. The error bars indicate s.e.

**Figure 2. Regional plots for the leptin-associated loci.**
Regional plots for the loci in or near *LEP* (a), *GCKR* (b), *SLC32A1* (c) and *CCNL1* (d), which reached genome-wide significance in the combined meta-analysis of Stage 1 and Stage 2 for BMI-unadjusted or BMI-adjusted leptin levels. The *COBLL1* locus (e) that reached P=1 × 10⁻⁶ with BMI-unadjusted and P=2 × 10⁻⁶ with BMI-adjusted leptin levels is also shown. For the locus near *LEP* (A), the rs10249476 SNP, located in a previously identified adipocyte-specific enhancer region, is indicated.

**Figure 3. Expression of murine homologues of genes.**
Expression of murine homologues of genes located within *Lep* (a,b), *Slc32a1* (c,d), *Gckr* (e,f), *Ccnl1* (g,h) and *Cobll1* loci (i,j) in PGAT and SCAT from 4-month-old mice fed chow (black bars) or high-fat diet (HFD; grey bars). Quantitative PCR (qPCR) transcripts were normalized using *ActB*, *Rplp0*, *Gapdh* and *Ppia* as housekeeping genes. N=5 mice per group. T-test. *P<0.05, **P<0.01 and ***P<0.001.

**Figure 4. Candidate gene knockdown studies in PGAT explants.**
Changes in *Lep* mRNA expression (a) and secretion into media (b) following candidate gene knockdown in PGAT explants following stimulation with insulin and dexamethasone for 12 h. Gene expression induced by stimulation with insulin and dexamethasone (c) N=5–13 mice per group (3 replicates/condition/mouse). Secreted adiponectin was measured as a control for non-leptin secretory function (d) N=5 mice per group. Two-way repeated measures analysis of variance (ANOVA). *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001.

See this image and copyright information in PMC

References

1. Ahima R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996). - PubMed
1. Montague C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997). - PubMed
1. Shah N. R. & Braverman E. R. Measuring adiposity in patients: the utility of body mass index (BMI), percent body fat, and leptin. PLoS ONE 7, e33308 (2012). - PMC - PubMed
1. Considine R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996). - PubMed
1. Liu J. et al. Leptinemia and its association with stroke and coronary heart disease in the Jackson Heart Study. Clin. Endocrinol. (Oxf.) 72, 32–37 (2010). - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous