KLB
is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference
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 
Published: November 2016

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.