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Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14372-14377. Epub 2016 Nov 28.

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.

Schumann G1, Liu C2,3,4, O'Reilly P5, Gao H6,7, Song P8,9, Xu B5, Ruggeri B5, Amin N10, Jia T5, Preis S4, Segura Lepe M6,11, Akira S12, Barbieri C13, Baumeister S14,15, Cauchi S16, Clarke TK17, Enroth S18, Fischer K19, Hällfors J20, Harris SE21,22, Hieber S23, Hofer E24,25, Hottenga JJ26, Johansson Å18, Joshi PK27, Kaartinen N28, Laitinen J29, Lemaitre R30, Loukola A20,31, Luan J32, Lyytikäinen LP33, Mangino M34,35, Manichaikul A36,37, Mbarek H26, Milaneschi Y38, Moayyeri A6,39,40, Mukamal K41, Nelson C42,43, Nettleton J44, Partinen E45, Rawal R46, Robino A47, Rose L48, Sala C13, Satoh T12, Schmidt R24, Schraut K27, Scott R49, Smith AV50, Starr JM21,51, Teumer A14,52, Trompet S53,54, Uitterlinden AG55,56, Venturini C34, Vergnaud AC6, Verweij N57, Vitart V58, Vuckovic D59, Wedenoja J31, Yengo L16, Yu B60,61, Zhang W6,62, Zhao JH49, Boomsma DI26, Chambers J6,62,63, Chasman DI48,64, Daniela T13, de Geus E26, Deary I21,65, Eriksson JG28,66,67,68,69, Esko T19, Eulenburg V70, Franco OH56, Froguel P16,71, Gieger C46, Grabe HJ72, Gudnason V50,73, Gyllensten U18, Harris TB74, Hartikainen AL75,76,77, Heath AC78, Hocking L79, Hofman A56, Huth C80, Jarvelin MR6,77,81,82, Jukema JW53, Kaprio J20,28,31, Kooner JS62,63,83, Kutalik Z84, Lahti J68,85,86, Langenberg C32, Lehtimäki T33, Liu Y87, Madden PA88, Martin N89, Morrison A60, Penninx B38, Pirastu N27,59, Psaty B30,90,91,92, Raitakari O93,94, Ridker P48,64, Rose R95, Rotter JI96, Samani NJ42,43, Schmidt H97, Spector TD34, Stott D98, Strachan D99, Tzoulaki I6,7,100, van der Harst P57,101,102, van Duijn CM10, Marques-Vidal P103, Vollenweider P103, Wareham NJ49, Whitfield JB89, Wilson J27,58, Wolffenbuttel B104, Bakalkin G105, Evangelou E6,100, Liu Y106,107, Rice KM108, Desrivières S5, Kliewer SA8,109, Mangelsdorf DJ110,9, Müller CP23, Levy D2,3, Elliott P111,7.

Author information

1
Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom; gunter.schumann@kcl.ac.uk davo.mango@utsouthwestern.edu p.elliott@imperial.ac.uk.
2
The Framingham Heart Study, Framingham, MA 01702.
3
The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD 20824.
4
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118.
5
Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom.
6
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
7
Medical Research Council-Public Health England Centre for Environment and Health, Imperial College London, London W2 1PG, United Kingdom.
8
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
9
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
10
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
11
Section of Bioinformatics, Bayer Pharma AG, 13342 Berlin, Germany.
12
Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
13
Division of Genetics and Cell Biology, San Raffaele Research Institute, 20132 Milan, Italy.
14
Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
15
Department of Epidemiology and Preventive Medicine, University of Regensburg, 93053 Regensburg, Germany.
16
CNRS UMR 8199, Lille Pasteur Institute, European Genomic Institute for Diabetes, Lille 2 University, 59000 Lille, France.
17
Divison of Psychiatry, University of Edinburgh, Edinburgh EH10 5HF, United Kingdom.
18
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 75108 Uppsala, Sweden.
19
Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia.
20
Institute for Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland.
21
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
22
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
23
Department of Psychiatry and Psychotherapy, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
24
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, 8036 Graz, Austria.
25
Institute of Medical Informatics, Statistics and Documentation, Medical University Graz, 8036 Graz, Austria.
26
Department of Biological Psychology, Vrije Universiteit Amsterdam and EMGO Institute for Health and Care Research, 1081 BT Amsterdam, The Netherlands.
27
Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom.
28
National Institute for Health and Welfare, 00271 Helsinki, Finland.
29
Quantified Employee-Unit, Finnish Institute of Occupational Health, 00250 Helsinki, Finland.
30
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101.
31
Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.
32
Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
33
Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
34
Department of Twin Research and Genetic Epidemiology, King's College, London SE1 7EH, United Kingdom.
35
National Institute for Health Research Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London SE1 9RT, United Kingdom.
36
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22903.
37
Biostatistics Section, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22903.
38
Department of Psychiatry, Institute for Health and Care Research (EMGO) Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit Amsterdam University Medical Center/Geestelijke Gezondheids Zorg (GGZ) inGeest, 1081 HL Amsterdam, The Netherlands.
39
Institute of Health Informatics, University College London, London NW1 2DA, United Kingdom.
40
Farr Institute of Health Informatics Research, University College London Institute of Health Informatics, London NW1 2DA, United Kingdom.
41
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.
42
Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom.
43
National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, United Kingdom.
44
Division of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Sciences Center, Houston, TX 77225.
45
Faculty of Medicine, University of Tartu, 50411 Tartu, Estonia.
46
Department of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
47
Institute for Maternal and Child Health-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Burlo Garofolo, 34137 Trieste, Italy.
48
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215.
49
Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
50
Research Institute, Icelandic Heart Association, 201 Kopavogur, Iceland.
51
Alzheimer Scotland Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
52
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany.
53
Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
54
Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
55
Department of internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
56
Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
57
Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
58
Medical Research Council Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
59
Department of Medical Sciences, University of Trieste, 34149 Trieste, Italy.
60
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77225.
61
Division of Epidemiology, University of Texas Health Science Center at Houston, Houston, TX 77225.
62
Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, United Kingdom.
63
Imperial College Healthcare National Health Service Trust, London W12 0HS, United Kingdom.
64
Harvard Medical School, Boston, MA 02115.
65
Psychology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
66
Department of General Practice and Primary Health Care, University of Helsinki, 00014 Helsinki, Finland.
67
Unit of General Practice, Helsinki University Central Hospital, 00014 Helsinki, Finland.
68
Folkhälsan Research Centre, Public Health Research, 00290 Helsinki, Finland.
69
Vasa Central Hospital, 65130 Vasa, Finland.
70
Institute for Biochemistry and Molecular Medicine, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
71
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London W12 0HR, United Kingdom.
72
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany.
73
Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
74
National Institute on Aging, NIH, Bethesda, MD 20892.
75
Department of Obstetrics and Gynecology, Oulu University Hospital, 90029 Oulu, Finland.
76
Medical Research Center, University of Oulu, 90014 Oulu, Finland.
77
Unit of Primary Care, Oulu University Hospital, 90220 Oulu, Finland.
78
Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
79
Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
80
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, D-85764 Neuherberg, Germany.
81
Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu FI-90014, Finland.
82
Biocenter Oulu, University of Oulu, Oulu FI-90014, Finland.
83
Faculty of Medicine, National Heart & Lung Institute, Cardiovascular Science, Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom.
84
Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudoise, 1010 Lausanne, Switzerland.
85
Collegium for Advanced Studies, University of Helsinki, 00014 Helsinki, Finland.
86
Institute of Behavioural Sciences, University of Helsinki, 00014 Helsinki, Finland.
87
Wake Forest School of Medicine, Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157.
88
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
89
Genetic Epidemiology, Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Brisbane QLD 4029, Australia.
90
Department of Epidemiology, University of Washington, Seattle, WA 98195.
91
Department of Health Services, University of Washington, Seattle, WA 98195.
92
Group Health Cooperative, Group Health Research Institute, Seattle, WA 98101.
93
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, University of Turku, Turku 20520, Finland.
94
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
95
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405.
96
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA 90509.
97
Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
98
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G31 2ER, United Kingdom.
99
Population Health Research Institute, St. George's, University of London, London SW17 0RE, United Kingdom.
100
Department of Hygiene and Epidemiology, University of Ioannina Medical School, 45110 Ioannina, Greece.
101
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
102
Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of The Netherlands-Netherlands Heart Institute, 3511GC Utrecht, The Netherlands.
103
Department of Medicine, Internal Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland.
104
Department of Endocrinology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
105
Division of Biological Research on Drug Dependence, Department of Pharmaceutical, Biosciences, Uppsala University, 751 24 Uppsala, Sweden.
106
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, 200032 Shanghai, People's Republic of China.
107
Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, 200032 Shanghai, People's Republic of China.
108
Department of Biostatistics, University of Washington, Seattle, WA 98195.
109
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
110
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390; gunter.schumann@kcl.ac.uk davo.mango@utsouthwestern.edu p.elliott@imperial.ac.uk.
111
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom; gunter.schumann@kcl.ac.uk davo.mango@utsouthwestern.edu p.elliott@imperial.ac.uk.

Abstract

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10-12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

KEYWORDS:

FGF21; alcohol consumption; human; mouse model; β-Klotho

PMID:
27911795
PMCID:
PMC5167198
DOI:
10.1073/pnas.1611243113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

B. Psaty serves on the Data and Safety Monitoring Board for a clinical trial funded by the manufacturer (Zoll LifeCor) and the Steering Committee of the Yale Open Data Access project funded by Johnson & Johnson. D.J.M. serves on the scientific advisory board of Metacrine. The other authors report no competing financial interests.

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