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

Schumann, G; Liu, C; O'Reilly, P; Gao, H; Song, P; Xu, B; Ruggeri, B; Amin, N; Jia, T; Preis, S; Segura Lepe, M; Akira, S; Barbieri, C; Baumeister, S; Cauchi, S; Clarke, T-K; Enroth, S; Fischer, K; Hällfors, J; Harris, SE; Hieber, S; Hofer, E; Hottenga, J-J; Johansson, Å; Joshi, PK; Kaartinen, N; Laitinen, J; Lemaitre, R; Loukola, A; Luan, J; Lyytikäinen, L-P; Mangino, M; Manichaikul, A; Mbarek, H; Milaneschi, Y; Moayyeri, A; Mukamal, K; Nelson, C; Nettleton, J; Partinen, E; Rawal, R; Robino, A; Rose, L; Sala, C; Satoh, T; Schmidt, R; Schraut, K; Scott, R; Smith, AV; Starr, JM; Teumer, A; Trompet, S; Uitterlinden, AG; Venturini, C; Vergnaud, A-C; Verweij, N; Vitart, V; Vuckovic, D; Wedenoja, J; Yengo, L; Yu, B; Zhang, W; Zhao, JH; Boomsma, DI; Chambers, J; Chasman, DI; Daniela, T; de Geus, E; Deary, I; Eriksson, JG; Esko, T; Eulenburg, V; Franco, OH; Froguel, P; Gieger, C; Grabe, HJ; Gudnason, V; Gyllensten, U; Harris, TB; Hartikainen, A-L; Heath, AC; Hocking, L; Hofman, A; Huth, C; Jarvelin, M-R; Jukema, JW; Kaprio, J; Kooner, JS; Kutalik, Z; Lahti, J; Langenberg, C; Lehtimäki, T; Liu, Y; Madden, PAF; Martin, N; Morrison, A; Penninx, B; Pirastu, N; Psaty, B; Raitakari, O; Ridker, P; Rose, R; Rotter, JI; Samani, NJ; Schmidt, H; Spector, TD; Stott, D; Strachan, D; Tzoulaki, I; van der Harst, P; van Duijn, CM; Marques-Vidal, P; Vollenweider, P; Wareham, NJ; Whitfield, JB; Wilson, J; Wolffenbuttel, B; Bakalkin, G; Evangelou, E; Rice, KM; Desrivières, S; Kliewer, SA; Mangelsdorf, DJ; Müller, CP; Levy, D; Elliott, P

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

journal contribution

posted on 2019-08-23, 15:25 authored by G Schumann, C Liu, P O'Reilly, H Gao, P Song, B Xu, B Ruggeri, N Amin, T Jia, S Preis, M Segura Lepe, S Akira, C Barbieri, S Baumeister, S Cauchi, T-K Clarke, S Enroth, K Fischer, J Hällfors, SE Harris, S Hieber, E Hofer, J-J Hottenga, Å Johansson, PK Joshi, N Kaartinen, J Laitinen, R Lemaitre, A Loukola, J Luan, L-P Lyytikäinen, M Mangino, A Manichaikul, H Mbarek, Y Milaneschi, A Moayyeri, K Mukamal, C Nelson, J Nettleton, E Partinen, R Rawal, A Robino, L Rose, C Sala, T Satoh, R Schmidt, K Schraut, R Scott, AV Smith, JM Starr, A Teumer, S Trompet, AG Uitterlinden, C Venturini, A-C Vergnaud, N Verweij, V Vitart, D Vuckovic, J Wedenoja, L Yengo, B Yu, W Zhang, JH Zhao, DI Boomsma, J Chambers, DI Chasman, T Daniela, E de Geus, I Deary, JG Eriksson, T Esko, V Eulenburg, OH Franco, P Froguel, C Gieger, HJ Grabe, V Gudnason, U Gyllensten, TB Harris, A-L Hartikainen, AC Heath, L Hocking, A Hofman, C Huth, M-R Jarvelin, JW Jukema, J Kaprio, JS Kooner, Z Kutalik, J Lahti, C Langenberg, T Lehtimäki, Y Liu, PAF Madden, N Martin, A Morrison, B Penninx, N Pirastu, B Psaty, O Raitakari, P Ridker, R Rose, JI Rotter, NJ Samani, H Schmidt, TD Spector, D Stott, D Strachan, I Tzoulaki, P van der Harst, CM van Duijn, P Marques-Vidal, P Vollenweider, NJ Wareham, JB Whitfield, J Wilson, B Wolffenbuttel, G Bakalkin, E Evangelou, KM Rice, S Desrivières, SA Kliewer, DJ Mangelsdorf, CP Müller, D Levy, P Elliott

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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Medical Research Council-funded UK Medical Bioinformatics Partnership Programme MR/L01632X/1. Other funding sources and acknowledgments for contributing authors and consortia can be found in SI Appendix

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Proceedings of the National Academy of Sciences U S A, 113 (50), pp. 14372-14377

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/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

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Proceedings of the National Academy of Sciences U S A

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National Academy of Sciences

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1091-6490

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2016

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2019-08-23

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https://doi.org/10.1073/pnas.1611243113

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This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1611243113/-/DCSupplemental.

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en

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https://leicester.figshare.com/account/articles/10231667

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

Funding

Medical Research Council-funded UK Medical Bioinformatics Partnership Programme MR/L01632X/1. Other funding sources and acknowledgments for contributing authors and consortia can be found in SI Appendix

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