TY - JOUR T1 - KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. JF - Proc Natl Acad Sci U S A Y1 - 2016 A1 - Schumann, Gunter A1 - Liu, Chunyu A1 - O'Reilly, Paul A1 - Gao, He A1 - Song, Parkyong A1 - Xu, Bing A1 - Ruggeri, Barbara A1 - Amin, Najaf A1 - Jia, Tianye A1 - Preis, Sarah A1 - Segura Lepe, Marcelo A1 - Akira, Shizuo A1 - Barbieri, Caterina A1 - Baumeister, Sebastian A1 - Cauchi, Stephane A1 - Clarke, Toni-Kim A1 - Enroth, Stefan A1 - Fischer, Krista A1 - Hällfors, Jenni A1 - Harris, Sarah E A1 - Hieber, Saskia A1 - Hofer, Edith A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Joshi, Peter K A1 - Kaartinen, Niina A1 - Laitinen, Jaana A1 - Lemaitre, Rozenn A1 - Loukola, Anu A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Mangino, Massimo A1 - Manichaikul, Ani A1 - Mbarek, Hamdi A1 - Milaneschi, Yuri A1 - Moayyeri, Alireza A1 - Mukamal, Kenneth A1 - Nelson, Christopher A1 - Nettleton, Jennifer A1 - Partinen, Eemil A1 - Rawal, Rajesh A1 - Robino, Antonietta A1 - Rose, Lynda A1 - Sala, Cinzia A1 - Satoh, Takashi A1 - Schmidt, Reinhold A1 - Schraut, Katharina A1 - Scott, Robert A1 - Smith, Albert Vernon A1 - Starr, John M A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Uitterlinden, André G A1 - Venturini, Cristina A1 - Vergnaud, Anne-Claire A1 - Verweij, Niek A1 - Vitart, Veronique A1 - Vuckovic, Dragana A1 - Wedenoja, Juho A1 - Yengo, Loic A1 - Yu, Bing A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Boomsma, Dorret I A1 - Chambers, John A1 - Chasman, Daniel I A1 - Daniela, Toniolo A1 - de Geus, Eco A1 - Deary, Ian A1 - Eriksson, Johan G A1 - Esko, Tõnu A1 - Eulenburg, Volker A1 - Franco, Oscar H A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Harris, Tamara B A1 - Hartikainen, Anna-Liisa A1 - Heath, Andrew C A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Huth, Cornelia A1 - Jarvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Kaprio, Jaakko A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Madden, Pamela A F A1 - Martin, Nicholas A1 - Morrison, Alanna A1 - Penninx, Brenda A1 - Pirastu, Nicola A1 - Psaty, Bruce A1 - Raitakari, Olli A1 - Ridker, Paul A1 - Rose, Richard A1 - Rotter, Jerome I A1 - Samani, Nilesh J A1 - Schmidt, Helena A1 - Spector, Tim D A1 - Stott, David A1 - Strachan, David A1 - Tzoulaki, Ioanna A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Marques-Vidal, Pedro A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wilson, James A1 - Wolffenbuttel, Bruce A1 - Bakalkin, Georgy A1 - Evangelou, Evangelos A1 - Liu, Yun A1 - Rice, Kenneth M A1 - Desrivières, Sylvane A1 - Kliewer, Steven A A1 - Mangelsdorf, David J A1 - Müller, Christian P A1 - Levy, Daniel A1 - Elliott, Paul AB -

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.

VL - 113 IS - 50 ER -