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


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Schumann, G; Liu, C; O'Reilly, P; Gao, H; Song, P; Xu, B; Ruggeri, B; Amin, N; Jia, T; Preis, S; Segura Lepe, M; Akira, S; Barbieri, C; Baumeister, S; Cauchi, S; Clarke, T-K; Enroth, S; Fischer, K; Hällfors, J; Harris, SE; Hieber, S; Hofer, E; Hottenga, J-J; Johansson, Å; Joshi, PK; Kaartinen, N; Laitinen, J; Lemaitre, R; Loukola, A; Luan, J; Lyytikäinen, L-P; Mangino, M; Manichaikul, A; Mbarek, H; Milaneschi, Y; Moayyeri, A; Mukamal, K; Nelson, C; Nettleton, J; Partinen, E; Rawal, R; Robino, A; Rose, L; Sala, C; Satoh, T; Schmidt, R; Schraut, K; Scott, R; Smith, AV; Starr, JM; Teumer, A; Trompet, S; Uitterlinden, AG; Venturini, C; Vergnaud, A-C; Verweij, N; Vitart, V; Vuckovic, D; Wedenoja, J; Yengo, L; Yu, B; Zhang, W; Zhao, JH; Boomsma, DI; Chambers, J; Chasman, DI; Daniela, T; de Geus, E; Deary, I; Eriksson, JG; Esko, T; Eulenburg, V; Franco, OH; Froguel, P; Gieger, C; Grabe, HJ; Gudnason, V; Gyllensten, U; Harris, TB; Hartikainen, A-L; Heath, AC; Hocking, L; Hofman, A; Huth, C; Jarvelin, M-R; Jukema, JW; Kaprio, J; Kooner, JS; Kutalik, Z; Lahti, J; Langenberg, C; Lehtimäki, T; Liu, Y; Madden, PAF; Martin, N; Morrison, A; Penninx, B; Pirastu, N; Psaty, B; Raitakari, O; Ridker, P; Rose, R; Rotter, JI; Samani, NJ; Schmidt, H; Spector, TD; Stott, D; Strachan, D; Tzoulaki, I; van der Harst, P; van Duijn, CM; Marques-Vidal, P; Vollenweider, P; Wareham, NJ; Whitfield, JB; Wilson, J; Wolffenbuttel, B; Bakalkin, G; Evangelou, E; Liu, Y; Rice, KM; Desrivières, S; Kliewer, SA; Mangelsdorf, DJ; Müller, CP; Levy, D; Elliott, P

Published Date

  • December 13, 2016

Published In

Volume / Issue

  • 113 / 50

Start / End Page

  • 14372 - 14377

PubMed ID

  • 27911795

Pubmed Central ID

  • 27911795

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1611243113


  • eng

Conference Location

  • United States