title: KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.
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.
authors.affiliation: 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.
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authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.|Medical Research Council-Public Health England Centre for Environment and Health, Imperial College London, London W2 1PG, United Kingdom.|Department of Hygiene and Epidemiology, University of Ioannina Medical School, 45110 Ioannina, Greece.
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authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.|Department of Genetics, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.|Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of The Netherlands-Netherlands Heart Institute, 3511GC Utrecht, The Netherlands.
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authors.initials: JB
authors.lastname: Whitfield
authors.affiliation: Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom.|Medical Research Council Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Wilson
authors.affiliation: Department of Endocrinology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
authors.forename: Bruce
authors.initials: B
authors.lastname: Wolffenbuttel
authors.affiliation: Division of Biological Research on Drug Dependence, Department of Pharmaceutical, Biosciences, Uppsala University, 751 24 Uppsala, Sweden.
authors.forename: Georgy
authors.initials: G
authors.lastname: Bakalkin
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom.|Department of Hygiene and Epidemiology, University of Ioannina Medical School, 45110 Ioannina, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Evangelou
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, 200032 Shanghai, People's Republic of China.|Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, 200032 Shanghai, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Rice
authors.affiliation: Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom.
authors.forename: Sylvane
authors.initials: S
authors.lastname: Desrivières
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.affiliation: 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.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: David J
authors.identifier: 0000-0002-4355-0796
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.affiliation: The Framingham Heart Study, Framingham, MA 01702.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD 20824.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: 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.|Medical Research Council-Public Health England Centre for Environment and Health, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics* / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000503:physiopathology; D004644:Emotions / Q000502:physiology; D005260:Female; D005346:Fibroblast Growth Factors / Q000502:physiology*; D055106:Genome-Wide Association Study; D006801:Humans; D000090265:Klotho Proteins; D008099:Liver / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide
chemical_list: C538995:KLB protein, human; C418622:Klb protein, mouse; D008565:Membrane Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins
keywords: FGF21; alcohol consumption; human; mouse model; β-Klotho