Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA.
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 beta-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 x 10(-12)). beta-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 beta-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.