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