KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference
Satoh T; Preis S; Segura Lepe M; Hällfors J; Zhao JH; Pirastu N; Wolffenbuttel B; Kliewer SA; Penninx B; Kaartinen N; Rotter JI; Levy D; Vollenweider P; Uitterlinden AG; Gao H; Huth C; Hofman A; Starr JM; Lyytikäinen LP; Chambers J; Tzoulaki I; O'Reilly P; Mangelsdorf DJ; Strachan D; Gieger C; Mbarek H; Samani NJ; Verweij N; Psaty B; Schraut K; Mangino M; Jia T; Schumann G; Kutalik Z; Eulenburg V; Lemaitre R; Harris SE; Laitinen J; Chasman DI; Eriksson JG; Harris TB; Jukema JW; Rice KM; Desrivières S; Boomsma DI; van Duijn CM; Ruggeri B; Jarvelin MR; Robino A; Lehtimäki T; Xu B; Wedenoja J; Heath AC; Joshi PK; Akira S; Rawal R; Hartikainen AL; Langenberg C; Froguel P; Enroth S; Milaneschi Y; Grabe HJ; Ridker P; Gudnason V; Smith AV; Teumer A; Moayyeri A; Schmidt H; Partinen E; Cauchi S; Bakalkin G; Liu C; Vuckovic D; Hieber S; Venturini C; Song P; de Geus E; Franco OH; Rose L; Baumeister S; Sala C; Hottenga JJ; Spector TD; Vergnaud AC; Rose R; Madden PA; Martin N; Clarke TK; Gyllensten U; Nettleton J; Trompet S; Fischer K; van der Harst P; Mukamal K; Luan J; Zhang W; Kooner JS; Whitfield JB; Wilson J; Lahti J; Barbieri C; Scott R; Kaprio J; Nelson C; Hocking L; Wareham NJ; Morrison A; Stott D; Marques-Vidal P; Raitakari O; Yengo L; Johansson å; Vitart V; Loukola A; Müller CP; Esko T; Amin N; Daniela T; Evangelou E; Elliott P; Schmidt R; Liu Y; Hofer E; Manichaikul A; Deary I; Yu B
https://urn.fi/URN:NBN:fi-fe2021042716232
Tiivistelmä
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.
Kokoelmat
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