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

  • Schumann G 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.
  • Liu C The Framingham Heart Study, Framingham, MA 01702.
  • O'Reilly P Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom.
  • Gao H Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
  • Song P Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Xu B Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom.
  • Ruggeri B Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom.
  • Amin N Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
  • Jia T Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom.
  • Preis S Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118.
  • Segura Lepe M Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
  • Akira S Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • Barbieri C Division of Genetics and Cell Biology, San Raffaele Research Institute, 20132 Milan, Italy.
  • Baumeister S Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
  • Cauchi S CNRS UMR 8199, Lille Pasteur Institute, European Genomic Institute for Diabetes, Lille 2 University, 59000 Lille, France.
  • Clarke TK Divison of Psychiatry, University of Edinburgh, Edinburgh EH10 5HF, United Kingdom.
  • Enroth S Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 75108 Uppsala, Sweden.
  • Fischer K Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia.
  • Hällfors J Institute for Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland.
  • Harris SE Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
  • Hieber S Department of Psychiatry and Psychotherapy, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
  • Hofer E Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, 8036 Graz, Austria.
  • Hottenga JJ Department of Biological Psychology, Vrije Universiteit Amsterdam and EMGO Institute for Health and Care Research, 1081 BT Amsterdam, The Netherlands.
  • Johansson Å Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 75108 Uppsala, Sweden.
  • Joshi PK Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom.
  • Kaartinen N National Institute for Health and Welfare, 00271 Helsinki, Finland.
  • Laitinen J Quantified Employee-Unit, Finnish Institute of Occupational Health, 00250 Helsinki, Finland.
  • Lemaitre R Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101.
  • Loukola A Institute for Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland.
  • Luan J Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Lyytikäinen LP Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
  • Mangino M Department of Twin Research and Genetic Epidemiology, King's College, London SE1 7EH, United Kingdom.
  • Manichaikul A Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22903.
  • Mbarek H Department of Biological Psychology, Vrije Universiteit Amsterdam and EMGO Institute for Health and Care Research, 1081 BT Amsterdam, The Netherlands.
  • Milaneschi Y 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.
  • Moayyeri A Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
  • Mukamal K Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.
  • Nelson C Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom.
  • Nettleton J Division of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Sciences Center, Houston, TX 77225.
  • Partinen E Faculty of Medicine, University of Tartu, 50411 Tartu, Estonia.
  • Rawal R Department of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Robino A Institute for Maternal and Child Health-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Burlo Garofolo, 34137 Trieste, Italy.
  • Rose L Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215.
  • Sala C Division of Genetics and Cell Biology, San Raffaele Research Institute, 20132 Milan, Italy.
  • Satoh T Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • Schmidt R Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, 8036 Graz, Austria.
  • Schraut K Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom.
  • Scott R Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Smith AV Research Institute, Icelandic Heart Association, 201 Kopavogur, Iceland.
  • Starr JM Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
  • Teumer A Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
  • Trompet S Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
  • Uitterlinden AG Department of internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
  • Venturini C Department of Twin Research and Genetic Epidemiology, King's College, London SE1 7EH, United Kingdom.
  • Vergnaud AC Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
  • Verweij N Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
  • Vitart V Medical Research Council Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
  • Vuckovic D Department of Medical Sciences, University of Trieste, 34149 Trieste, Italy.
  • Wedenoja J Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.
  • Yengo L CNRS UMR 8199, Lille Pasteur Institute, European Genomic Institute for Diabetes, Lille 2 University, 59000 Lille, France.
  • Yu B Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77225.
  • Zhang W Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
  • Zhao JH Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Boomsma DI Department of Biological Psychology, Vrije Universiteit Amsterdam and EMGO Institute for Health and Care Research, 1081 BT Amsterdam, The Netherlands.
  • Chambers J Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
  • Chasman DI Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215.
  • Daniela T Division of Genetics and Cell Biology, San Raffaele Research Institute, 20132 Milan, Italy.
  • de Geus E Department of Biological Psychology, Vrije Universiteit Amsterdam and EMGO Institute for Health and Care Research, 1081 BT Amsterdam, The Netherlands.
  • Deary I Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
  • Eriksson JG National Institute for Health and Welfare, 00271 Helsinki, Finland.
  • Esko T Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia.
  • Eulenburg V Institute for Biochemistry and Molecular Medicine, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
  • Franco OH Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
  • Froguel P CNRS UMR 8199, Lille Pasteur Institute, European Genomic Institute for Diabetes, Lille 2 University, 59000 Lille, France.
  • Gieger C Department of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Grabe HJ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany.
  • Gudnason V Research Institute, Icelandic Heart Association, 201 Kopavogur, Iceland.
  • Gyllensten U Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 75108 Uppsala, Sweden.
  • Harris TB National Institute on Aging, NIH, Bethesda, MD 20892.
  • Hartikainen AL Department of Obstetrics and Gynecology, Oulu University Hospital, 90029 Oulu, Finland.
  • Heath AC Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
  • Hocking L Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
  • Hofman A Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
  • Huth C Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, D-85764 Neuherberg, Germany.
  • Jarvelin MR Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
  • Jukema JW Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
  • Kaprio J Institute for Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland.
  • Kooner JS Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, United Kingdom.
  • Kutalik Z Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudoise, 1010 Lausanne, Switzerland.
  • Lahti J Folkhälsan Research Centre, Public Health Research, 00290 Helsinki, Finland.
  • Langenberg C Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Lehtimäki T Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
  • Liu Y Wake Forest School of Medicine, Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157.
  • Madden PA Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
  • Martin N Genetic Epidemiology, Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Brisbane QLD 4029, Australia.
  • Morrison A Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77225.
  • Penninx B 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.
  • Pirastu N Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom.
  • Psaty B Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101.
  • Raitakari O Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, University of Turku, Turku 20520, Finland.
  • Ridker P Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215.
  • Rose R Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405.
  • Rotter JI Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA 90509.
  • Samani NJ Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom.
  • Schmidt H Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
  • Spector TD Department of Twin Research and Genetic Epidemiology, King's College, London SE1 7EH, United Kingdom.
  • Stott D Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G31 2ER, United Kingdom.
  • Strachan D Population Health Research Institute, St. George's, University of London, London SW17 0RE, United Kingdom.
  • Tzoulaki I Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
  • van der Harst P Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
  • van Duijn CM Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
  • Marques-Vidal P Department of Medicine, Internal Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland.
  • Vollenweider P Department of Medicine, Internal Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland.
  • Wareham NJ Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
  • Whitfield JB Genetic Epidemiology, Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Brisbane QLD 4029, Australia.
  • Wilson J Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom.
  • Wolffenbuttel B Department of Endocrinology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
  • Bakalkin G Division of Biological Research on Drug Dependence, Department of Pharmaceutical, Biosciences, Uppsala University, 751 24 Uppsala, Sweden.
  • Evangelou E Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.
  • Liu Y Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, 200032 Shanghai, People's Republic of China.
  • Rice KM Department of Biostatistics, University of Washington, Seattle, WA 98195.
  • Desrivières S Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom.
  • Kliewer SA Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Mangelsdorf DJ 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.
  • Müller CP Department of Psychiatry and Psychotherapy, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
  • Levy D The Framingham Heart Study, Framingham, MA 01702.
  • Elliott P 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.
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  • 2016-12-03
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2016
FGF21
alcohol consumption
human
mouse model
β-Klotho
Alcohol Drinking
Animals
Behavior, Animal
Brain
Emotions
Female
Fibroblast Growth Factors
Genome-Wide Association Study
Humans
Liver
Male
Membrane Proteins
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Polymorphism, Single Nucleotide
English 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.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/291014
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