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

Gunter Schumann, Chunyu Liu, Paul O'Reilly, He Gao, Parkyong Song, Bing Xu, Barbara Ruggeri, Najaf Amin, Tianye Jia, Sarah Preis, Marcelo Segura Lepe, Shizuo Akira, Caterina Barbieri, Sebastian Baumeister, Stephane Cauchi, Toni-Kim Clarke, Stefan Enroth, Krista Fischer, Jenni Hällfors, Sarah E HarrisSaskia Hieber, Edith Hofer, Jouke-Jan Hottenga, Åsa Johansson, Peter K Joshi, Niina Kaartinen, Jaana Laitinen, Rozenn Lemaitre, Anu Loukola, Jian'an Luan, Leo-Pekka Lyytikäinen, Massimo Mangino, Ani Manichaikul, Hamdi Mbarek, Yuri Milaneschi, Alireza Moayyeri, Kenneth Mukamal, Christopher Nelson, Jennifer Nettleton, Eemil Partinen, Rajesh Rawal, Antonietta Robino, Lynda Rose, Cinzia Sala, Takashi Satoh, Reinhold Schmidt, Katharina Schraut, Robert Scott, Albert Vernon Smith, John M Starr, Alexander Teumer, Stella Trompet, André G Uitterlinden, Cristina Venturini, Anne-Claire Vergnaud, Niek Verweij, Veronique Vitart, Dragana Vuckovic, Juho Wedenoja, Loic Yengo, Bing Yu, Weihua Zhang, Jing Hua Zhao, Dorret I Boomsma, John Chambers, Daniel I Chasman, Toniolo Daniela, Eco de Geus, Ian Deary, Johan G Eriksson, Tõnu Esko, Volker Eulenburg, Oscar H Franco, Philippe Froguel, Christian Gieger, Hans J Grabe, Vilmundur Gudnason, Ulf Gyllensten, Tamara B Harris, Anna-Liisa Hartikainen, Andrew C Heath, Lynne Hocking, Albert Hofman, Cornelia Huth, Marjo-Riitta Jarvelin, J Wouter Jukema, Jaakko Kaprio, Jaspal S Kooner, Zoltan Kutalik, Jari Lahti, Claudia Langenberg, Terho Lehtimäki, Yongmei Liu, Pamela A F Madden, Nicholas Martin, Alanna Morrison, Brenda Penninx, Nicola Pirastu, Bruce Psaty, Olli Raitakari, Paul Ridker, Richard Rose, Jerome I Rotter, Nilesh J Samani, Helena Schmidt, Tim D Spector, David Stott, David Strachan, Ioanna Tzoulaki, Pim van der Harst, Cornelia M van Duijn, Pedro Marques-Vidal, Peter Vollenweider, Nicholas J Wareham, John B Whitfield, James Wilson, Bruce Wolffenbuttel, Georgy Bakalkin, Evangelos Evangelou, Yun Liu, Kenneth M Rice, Sylvane Desrivières, Steven A Kliewer, David J Mangelsdorf, Christian P Müller, Daniel Levy, Paul Elliott

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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.

Original languageEnglish
Pages (from-to)14372-14377
Number of pages6
JournalPNAS
Volume113
Issue number50
Early online date28 Nov 2016
DOIs
Publication statusPublished - 13 Dec 2016

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    Schumann, G., Liu, C., O'Reilly, P., Gao, H., Song, P., Xu, B., Ruggeri, B., Amin, N., Jia, T., Preis, S., Segura Lepe, M., Akira, S., Barbieri, C., Baumeister, S., Cauchi, S., Clarke, T-K., Enroth, S., Fischer, K., Hällfors, J., ... Elliott, P. (2016). KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. PNAS, 113(50), 14372-14377. https://doi.org/10.1073/pnas.1611243113