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

著者: Günter Schumann, Chunyu Liu, Paul F. O’Reilly, He Gao, Parkyong Song, Bing Xu, Barbara Ruggeri, Najaf Amin, Tianye Jia, Sarah R. Preis, Marcelo Segura Lepe, Shizuo Akira, Caterina Barbieri, Sebastian E. Baumeister, Stéphane Cauchi, Toni‐Kim Clarke, Stefan Enroth, Krista Fischer, Jenni Hällfors, Sarah E. Harris, Saskia Hieber, Edith Hofer, Jouke‐Jan Hottenga, Åsa Johansson, Peter K. Joshi, Niina E. Kaartinen, Jaana Laitinen, Rozenn N. Lemaître, Anu Loukola, Jian’an Luan, Leo‐Pekka Lyytikäinen, Massimo Mangino, Ani Manichaikul, Hamdi Mbarek, Yuri Milaneschi, Alireza Moayyeri, Kenneth J. Mukamal, Christopher Nelson, Jennifer A. Nettleton, Eemil Partinen, Rajesh Rawal, Antonietta Robino, Lynda M. Rose, Cinzia Sala, Takashi Satoh, Reinhold Schmidt, Katharina E. Schraut, Robert Scott, Albert V. Smith, John M. Starr, Alexander Teumer, Stella Trompet, André G. Uitterlinden, Cristina Venturini, Anne‐Claire Vergnaud, Niek Verweij, Véronique Vitart, Dragana Vuckovic, Juho Wedenoja, Loïc Yengo, Bing Yu, Weihua Zhang, Jing Hua Zhao, Dorret I. Boomsma, John C. Chambers, Daniel I. Chasman, Daniela Toniolo, Eco J. C. de Geus, Ian J. Deary, Johan G. Eriksson, Tõnu Esko, Volker Eulenburg, Oscar H. Franco, Philippe Froguel, Christian Gieger, Hans J. Grabe, Vilmundur Guðnason, Ulf Gyllensten, Tamara B. Harris, Anna-Liisa Hartikainen, Andrew C. Heath, Lynne J. Hocking, Albert Hofman, Cornelia Huth, Marjo‐Riitta Järvelin, J. Wouter Jukema, Jaakko Kaprio, Jaspal S. Kooner, Zoltán Kutalik, Jari Lahti, Claudia Langenberg, Terho Lehtimäki, Ching‐Ti Liu, Pamela A. F. Madden, Nicholas G. Martin, Alanna C. Morrison, Brenda W.J.H. Penninx, Nicola Pirastu, Bruce M. Psaty, Olli T. Raitakari, Paul M. Ridker, Richard J. Rose, Jerome I. Rotter, Nilesh J. Samani, Helena Schmidt, Tim D. Spector, David J. Stott, David P. Strachan, Ioanna Tzoulaki, Pim van der Harst, Cornelia M. van Duijn, Pedro Marques‐Vidal, Péter Vollenweider, Nicholas J. Wareham, John B. Whitfield, James F. Wilson, Bruce H. R. Wolffenbuttel, Georgy Bakalkin, Εvangelos Εvangelou, Yun Liu, Kenneth Rice, Sylvane Desrivières, Steven A. Kliewer, David J. Mangelsdorf, Christian P. Müller, Daniel Levy, Paul Elliott - Proceedings of the National Academy of Sciences, PNAS 2016 被引用: 253

Significance Alcohol is a widely consumed drug in western societies that can lead to addiction. A small shift in consumption can have dramatic consequences on public health. We performed the largest genome-wide association metaanalysis and replication study to date (>105,000 individuals) and identified a genetic basis for alcohol consumption during nonaddictive drinking. We found that a locus in the gene encoding β-Klotho is associated with alcohol consumption. β-Klotho is an essential receptor component for the endocrine FGFs, FGF19 and FGF21. Using mouse models and pharmacologic administration of FGF21, we show that β-Klotho in the brain controls alcohol drinking. These findings reveal a mechanism regulating alcohol consumption in humans that may be pharmacologically tractable for reducing alcohol intake.