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

Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, Ruggeri B, Amin N, Jia T, Preis S, Lepe MS, Akira S, Barbieri C, Baumeister S, Cauchi S, Clarke TK, Enroth S, Fischer K, Hallfors J, Harris SE, Hieber S, Hofer E, Hottenga JJ, Johansson A, Joshi P, Kaartinen N, Laitinen J, Lemaitre R, Loukola A, Luan J, Lyytikainen LP, Mangino M, Manichaikul A, Mbarek H, Milaneschi Y, Moayyeri A, Mukamal K, Nelson C, Nettleton J, Partinen E, Rawal R, Robino A, Rose L, Sala C, Satoh T, Schmidt R, Schrautz K, Scott R, Smith AV, Starr JM, Teumer A, Trompet S, Uitterlinden AG, Venturini C, Vergnaud AC, Verweij N, Vitart V, Vuckovic D, Wedenoja J, Yengo L, Yu B, Zhang W, Zhao JH, Boomsma DI, Chambers J, Chasman DI, Daniela T, De Geus E, Deary I, Eriksson JG, Esko T, Eulenburg V, Franco OH, Froguel P, Gieger C, Grabe HJ, Gudnason V, Gyllensten U, Harris TB, Hartikainen AL, Heath AC, Hocking L, Hofman A, Huth C, Jarvelin MR, Jukema JW, Kaprio J, Kooner JS, Kutalik Z, Lahti J, Langenberg C, Lehtimaki T, Liu Y, Madden PAF, Martin N, Morrison A, Penninx B, Pirastu N, Psaty B, Raitakari O, Ridker P, Rose R, Rotter JI, Samani NJ, Schmidt H, Spector TD, Stott D, Strachan D, Tzoulaki I, Van Der Harst P, Van Duijn CM, Marques-Vidal P, Vollenweider P, Wareham NJ, Whitfield JB, Wilson J, Wolffenbuttel B, Bakalkin G, Evangelou E, Liu Y, Rice KM, Desrivieres S, Kliewer SA, Mangelsdorf DJ, Müller CP, Levy D, Elliott P (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 113

Pages Range: 14372-14377

Journal Issue: 50

DOI: 10.1073/pnas.1611243113

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 ?-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). ?-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 ?-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 with CRIS profile

Involved external institutions

University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Harvard University United States (USA) (US) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) Ministry of Education of the People's Republic of China China (CN) University of Washington United States (USA) (US) King’s College London United Kingdom (GB) Framingham Heart Study United States (USA) (US) University of Texas Southwestern Medical Center (UT Southwestern) United States (USA) (US) Indiana University United States (USA) (US) University of California Los Angeles (UCLA) United States (USA) (US) University of Leicester United Kingdom (GB) Erasmus University Medical Center (MC) Netherlands (NL) Boston University United States (USA) (US) Osaka University / 大阪大学 Japan (JP) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) Italy (IT) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Université de Lille (ULille) / University of Lille Nord de France / Université Lille Nord de France / Université Lille II France (FR) University of Edinburgh United Kingdom (GB) Uppsala University Sweden (SE) University of Tartu Estonia (EE) Helsingin yliopisto / University of Helsinki Finland (FI) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) National Institute for Health and Welfare (THL) Finland (FI) Finnish Institute of Occupational Health (FIOH) / Työterveyslaitos (TTL) Finland (FI) University of Cambridge United Kingdom (GB) Fimlab Laboratories Finland (FI) University of Virginia (UVA) United States (USA) (US) Beth Israel Deaconess Medical Center (BIDMC) United States (USA) (US) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Istituto di ricovero e cura a carattere scientifico (IRCCS) Italy (IT) Brigham and Women's Hospital (BWH) United States (USA) (US) Icelandic Heart Association (IHA) Iceland (IS) Leiden University Netherlands (NL) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Università degli Studi di Trieste Italy (IT) National Institute on Aging (NIA) United States (USA) (US) Oulu University Hospital Finland (FI) Washington University in St. Louis United States (USA) (US) University of Aberdeen United Kingdom (GB) Ealing Hospital NHS Trust United Kingdom (GB) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) Finnish Institute for Health and Welfare / Terveyden ja Hyvinvoinnin Laitos (THL) Finland (FI) Wake Forest University United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Turku / Turun yliopisto Finland (FI) University of Glasgow United Kingdom (GB) St George's, University of London (SGUL) / St George's Hospital Medical School United Kingdom (GB)

How to cite

APA:

Schumann, G., Liu, C., O'Reilly, P., Gao, H., Song, P., Xu, B.,... Elliott, P. (2016). KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. Proceedings of the National Academy of Sciences of the United States of America, 113(50), 14372-14377. https://doi.org/10.1073/pnas.1611243113

MLA:

Schumann, Gunter, et al. "KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference." Proceedings of the National Academy of Sciences of the United States of America 113.50 (2016): 14372-14377.

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