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

Schumann, G. 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), pp. 14372-14377. (doi: 10.1073/pnas.1611243113) (PMID:27911795) (PMCID:PMC5167198)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stott J, Professor David
Authors: 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, S. E., Hieber, S., Hofer, E., Hottenga, J.-J., Johansson, Å., Joshi, P. K., Kaartinen, N., Laitinen, J., Lemaitre, R., Loukola, A., Luan, J.'a., 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, A. V., Starr, J. M., Teumer, A., Trompet, S., Uitterlinden, A. G., Venturini, C., Vergnaud, A.-C., Verweij, N., Vitart, V., Vuckovic, D., Wedenoja, J., Yengo, L., Yu, B., Zhang, W., Zhao, J. H., Boomsma, D. I., Chambers, J., Chasman, D. I., Daniela, T., de Geus, E., Deary, I., Eriksson, J. G., Esko, T., Eulenburg, V., Franco, O. H., Froguel, P., Gieger, C., Grabe, H. J., Gudnason, V., Gyllensten, U., Harris, T. B., Hartikainen, A.-L., Heath, A. C., Hocking, L., Hofman, A., Huth, C., Jarvelin, M.-R., Jukema, J. W., Kaprio, J., Kooner, J. S., Kutalik, Z., Lahti, J., Langenberg, C., Lehtimäki, T., Liu, Y., Madden, P. A.F., Martin, N., Morrison, A., Penninx, B., Pirastu, N., Psaty, B., Raitakari, O., Ridker, P., Rose, R., Rotter, J. I., Samani, N. J., Schmidt, H., Spector, T. D., Stott, D., Strachan, D., Tzoulaki, I., van der Harst, P., van Duijn, C. M., Marques-Vidal, P., Vollenweider, P., Wareham, N. J., Whitfield, J. B., Wilson, J., Wolffenbuttel, B., Bakalkin, G., Evangelou, E., Liu, Y., Rice, K. M., Desrivières, S., Kliewer, S. A., Mangelsdorf, D. J., Müller, C. P., Levy, D., and Elliott, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:28 November 2016
Copyright Holders:Copyright © 2016 National Academy of Sciences
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 113(50): 14372-14377
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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