KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.
Segura Lepe, M
de Geus, E
van der Harst, P
van Duijn, CM
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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Schumann, G., Liu, C., O'Reilly, P., Gao, H., Song, P., Xu, B., Ruggeri, B., et al. (2016). KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.. Proceedings of the National Academy of Sciences of the United States of America, 113 (50), 14372-14377. https://doi.org/10.1073/pnas.1611243113
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.
FGF21, alcohol consumption, human, mouse model, β-Klotho
External DOI: https://doi.org/10.1073/pnas.1611243113
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262636