KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference
- Schumann, Gunter;
- Liu, Chunyu;
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- Jia, Tianye;
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- Barbieri, Caterina;
- Baumeister, Sebastian;
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- Clarke, Toni-Kim;
- Enroth, Stefan;
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- Manichaikul, Ani;
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- de Geus, Eco;
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- Eulenburg, Volker;
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- Froguel, Philippe;
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- Hartikainen, Anna-Liisa;
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- Hofman, Albert;
- Huth, Cornelia;
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- Langenberg, Claudia;
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- Liu, Yongmei;
- Madden, Pamela AF;
- Martin, Nicholas;
- Morrison, Alanna;
- Penninx, Brenda;
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- Psaty, Bruce;
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- Mangelsdorf, David J;
- Müller, Christian P;
- Levy, Daniel;
- Elliott, Paul
- et al.
Published Web Location
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167198/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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