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

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  • Gunter Schumann
  • Chunyu Liu
  • Paul O'Reilly
  • He Gao
  • Parkyong Song
  • Bing Xu
  • Barbara Ruggeri
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  • Tianye Jia
  • Sarah Preis
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Original languageEnglish
JournalProceedings of the National Academy of Sciences
Early online date28 Nov 2016
DOIs
Publication statusPublished - 13 Dec 2016

Abstract

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.

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