KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.
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- Authors
- Schumann, Gunter; Liu, Chunyu; O'Reilly, Paul; Gao, He; Song, Parkyong; Xu, Bing; Ruggeri, Barbara; Amin, Najaf; Jia, Tianye; Preis, Sarah; Segura Lepe, Marcelo; Akira, Shizuo; Barbieri, Caterina; Baumeister, Sebastian; Cauchi, Stephane; Clarke, Toni-Kim; Enroth, Stefan; Fischer, Krista; Hällfors, Jenni; Harris, Sarah E; Hieber, Saskia; Hofer, Edith; Hottenga, Jouke-Jan; Johansson, Åsa; Joshi, Peter K; Kaartinen, Niina; Laitinen, Jaana; Lemaitre, Rozenn; Loukola, Anu; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Mangino, Massimo; Manichaikul, Ani; Mbarek, Hamdi; Milaneschi, Yuri; Moayyeri, Alireza; Mukamal, Kenneth; Nelson, Christopher; Nettleton, Jennifer; Partinen, Eemil; Rawal, Rajesh; Robino, Antonietta; Rose, Lynda; Sala, Cinzia; Satoh, Takashi; Schmidt, Reinhold; Schraut, Katharina; Scott, Robert; Smith, Albert Vernon; Starr, John M; Teumer, Alexander; Trompet, Stella; Uitterlinden, André G; Venturini, Cristina; Vergnaud, Anne-Claire; Verweij, Niek; Vitart, Veronique; Vuckovic, Dragana; Wedenoja, Juho; Yengo, Loic; Yu, Bing; Zhang, Weihua; Zhao, Jing Hua; Boomsma, Dorret I; Chambers, John; Chasman, Daniel I; Daniela, Toniolo; de Geus, Eco; Deary, Ian; Eriksson, Johan G; Esko, Tõnu; Eulenburg, Volker; Franco, Oscar H; Froguel, Philippe; Gieger, Christian; Grabe, Hans J; Gudnason, Vilmundur; Gyllensten, Ulf; Harris, Tamara B; Hartikainen, Anna-Liisa; Heath, Andrew C; Hocking, Lynne; Hofman, Albert; Huth, Cornelia; Jarvelin, Marjo-Riitta; Jukema, J Wouter; Kaprio, Jaakko; Kooner, Jaspal S; Kutalik, Zoltan; Lahti, Jari; Langenberg, Claudia; Lehtimäki, Terho; Liu, Yongmei; Madden, Pamela A F; Martin, Nicholas; Morrison, Alanna; Penninx, Brenda; Pirastu, Nicola; Psaty, Bruce; Raitakari, Olli; Ridker, Paul; Rose, Richard; Rotter, Jerome I; Samani, Nilesh J; Schmidt, Helena; Spector, Tim D; Stott, David; Strachan, David; Tzoulaki, Ioanna; van der Harst, Pim; van Duijn, Cornelia M; Marques-Vidal, Pedro; Vollenweider, Peter; Wareham, Nicholas J; Whitfield, John B; Wilson, James; Wolffenbuttel, Bruce; Bakalkin, Georgy; Evangelou, Evangelos; Liu, Yun; Rice, Kenneth M; Desrivières, Sylvane; Kliewer, Steven A; Mangelsdorf, David J; Müller, Christian P; Levy, Daniel; Elliott, Paul
- Year
- 2016
- Journal
- Proceedings of the National Academy of Sciences of the United States of America
- PMID
- 27911795
- DOI
- 10.1073/pnas.1611243113
- PMCID
- PMC5167198
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). 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.
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