Journal Article

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

Luan, Jian’an, Nelson, Christopher, Strachan, David, Gudnason, Vilmundur, Preis, Sarah, Ruggeri, Barbara, Kaartinen, Niina, Amin, Najaf, Rose, Lynda, Liu, Yongmei, Wilson, James, Barbieri, Caterina, Hieber, Saskia, Milaneschi, Yuri, Elliott, Paul, Deary, Ian, Liu, Yun, Hofer, Edith, Robino, Antonietta, Boomsma, Dorret I., Esko, Tõnu, Vollenweider, Peter, Kaprio, Jaakko, Fische, Kristar, Huth, Cornelia, Akira, Shizuo, van der Harst, Pim, Schmidt, Helena, Samani, Nilesh J., Gyllensten, Ulf, Jukema, J. Wouter, Nettleton, Jennifer, Langenberg, Claudia, Wedenoja, Juho, Kutalik, Zoltan, Chambers, John, Marques-Vidal, Pedro, Gao, He, Yengo, Loic, Joshi, Peter K., Eriksson, Johan G., Gieger, Christian, Lemaitre, Rozenn, Wolffenbuttel, Bruce, Yu, Bing, Schumann, Gunter, Spector, Tim D., Liu, Chunyu, Bakalkin, Georgy, Schmidt, Reinhold, Uitterlinden, André G., Franco, Oscar H., Kooner, Jaspal S., Hartikainen, Anna-Liisa, Heath, Andrew C., Levy, Daniel, Jarvelin, Marjo-Riitta, Rose, Richard, Rawal, Rajesh, Loukola, Anu, Scott, Robert, Vuckovic, Dragana, Mbarek, Hamdi, Starr, John M., Evangelou, Evangelos, van Duijn, Corneli

2016

Overview

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.

• Publisher: National Academy of Sciences
• Subject: alcohol consumption / Alcohol Drinking - genetics / Alcohol Drinking - physiopathology / Animals / Behavior, Animal - physiology / beta-Klotho / Biological Sciences / Brain - physiopathology / Emotions - physiology / Female / FGF21 / Fibroblast Growth Factors - physiology / Genetics / Genome-Wide Association Study / human / Humans / Klotho Proteins / Liver - physiopathology / Male / Membrane Proteins - deficiency / Membrane Proteins - genetics / Membrane Proteins - physiology / Mice / Mice, 129 Strain / Mice, Inbred C57BL / Mice, Knockout / mouse model / Polymorphism, Single Nucleotide