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

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.