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.

Additional Metadata
Keywords Alcohol consumption, FGF21, Human, Mouse model, β-Klotho
Persistent URL dx.doi.org/10.1073/pnas.1611243113, hdl.handle.net/1765/97377
Journal Proceedings of the National Academy of Sciences of the United States of America
Citation
Schumann, G, Liu, C. (Chunyu), O'Reilly, P.F, Gao, H. (He), Song, P. (Parkyong), Xu, B. (Bing), … Elliott, P. (2016). KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. In Proceedings of the National Academy of Sciences of the United States of America (Vol. 113, pp. 14372–14377). doi:10.1073/pnas.1611243113