Open AccessKLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference
Author(s) -
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,
ToniKim Clarke,
Stefan Enroth,
Krista Fischer,
Jenni Hällfors,
Sarah E. Harris,
Saskia Hieber,
Edith Hofer,
JoukeJan Hottenga,
Åsa Johansson,
Peter K. Joshi,
Niina E. Kaartinen,
Jaana Laitinen,
Rozenn N. Lemaître,
Anu Loukola,
Jian’an Luan,
LeoPekka 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,
AnneClaire 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,
Tōnu 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,
MarjoRiitta Järvelin,
J. Wouter Jukema,
Jaakko Kaprio,
Jaspal S. Kooner,
Zoltán Kutalik,
Jari Lahti,
Claudia Langenberg,
Terho Lehtimäki,
ChingTi 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 MarquesVidal,
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
Publication year - 2016
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1611243113
Subject(s) - fgf21 , klotho , alcohol , alcohol consumption , biology , medicine , genetics , fibroblast growth factor , receptor , biochemistry , kidney
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.
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