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