Research Article

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

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PNAS first published November 28, 2016; https://doi.org/10.1073/pnas.1611243113

  1. Contributed by David J. Mangelsdorf, October 18, 2016 (sent for review July 11, 2016; reviewed by Robert Adron Harris and Victor Hesselbrock)

Significance

Alcohol is a widely consumed drug in western societies that can lead to addiction. A small shift in consumption can have dramatic consequences on public health. We performed the largest genome-wide association metaanalysis and replication study to date (>105,000 individuals) and identified a genetic basis for alcohol consumption during nonaddictive drinking. We found that a locus in the gene encoding β-Klotho is associated with alcohol consumption. β-Klotho is an essential receptor component for the endocrine FGFs, FGF19 and FGF21. Using mouse models and pharmacologic administration of FGF21, we show that β-Klotho in the brain controls alcohol drinking. These findings reveal a mechanism regulating alcohol consumption in humans that may be pharmacologically tractable for reducing alcohol intake.

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.

Footnotes

  • ↵1G.S., C. Liu, P.O., H.G., P.S., S.D., S.A.K., D.J.M., C.P.M., D.L., and P.E. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: gunter.schumann{at}kcl.ac.uk, davo.mango{at}utsouthwestern.edu, or p.elliott{at}imperial.ac.uk.

  • Author contributions: G.S., C. Liu, P.S., J. Laitinen, T.S., R. Schmidt, J.M.S., S.T., D.I.B., J.C., D.I.C., T.D., E.d.G., I.D., J.G.E., T.E., O.H.F., P.F., C.G., H.J.G., V.G., U.G., T.B.H., A.-L.H., A.C.H., A.H., C.H., M.-R.J., J.W.J., J.K., J.S.K., T.L., Yongmei Liu, P.A.F.M., N.M., A. Morrison, B. Penninx, N.P., B. Psaty, O.R., P.R., R. Rose, J.I.R., N.J.S., H.S., T.D.S., D. Stott, D. Strachan, I.T., P.v.d.H., C.M.v.D., P.M.-V., N.J.W., J. Wilson, B.W., S.A.K., D.J.M., C.P.M., D.L., and P.E. designed research; P.S. and G.B. performed research; G.S., C. Liu, P.O., H.G., P.S., B.X., B.R., N.A., T.J., S.P., M.S.L., S.A., C.B., S.B., S.C., T.-K.C., S.E., K.F., J.H., S.E.H., S.H., E.H., J.-J.H., A.J., P.K.J., N.K., J. Laitinen, R.L., A.L., J. Luan, L.-P.L., M.M., A. Manichaikul, H.M., Y.M., A. Moayyeri, K.M., C.N., J.N., E.P., R. Rawal, A.R., L.R., C.S., T.S., K.S., R. Scott, A.V.S., J.M.S., A.T., S.T., A.G.U., C.V., A.-C.V., N.V., V.V., D.V., J. Wedenoja, L.Y., B.Y., W.Z., J.H.Z., V.E., C.G., A.C.H., L.H., Z.K., J. Lahti, C. Langenberg, Yongmei Liu, N.M., N.P., D. Strachan, P.V., J.B.W., G.B., E.E., Yun Liu, K.M.R., S.D., S.A.K., D.J.M., C.P.M., D.L., and P.E. analyzed data; C. Liu, S.E.H., N.K., J. Luan, K.M., J.N., C.S., R. Schmidt, J.M.S., A.G.U., C.V., V.V., D.I.B., J.C., D.I.C., E.d.G., I.D., T.E., O.H.F., P.F., V.G., U.G., T.B.H., A.-L.H., A.C.H., L.H., A.H., C.H., M.-R.J., J.W.J., J.K., J.S.K., T.L., Yongmei Liu, P.A.F.M., N.M., A. Morrison, B. Penninx, B. Psaty, O.R., P.R., R. Rose, J.I.R., N.J.S., H.S., D. Stott, D. Strachan, I.T., P.v.d.H., C.M.v.D., P.M.-V., N.J.W., J. Wilson, B.W., G.B., and Yun Liu contributed to data acquisition; and G.S., C. Liu, P.O., H.G., P.S., B.X., B.R., E.E., S.D., S.A.K., D.J.M., C.P.M., D.L., and P.E. wrote the paper.

  • Reviewers: R.A.H., The University of Texas at Austin; and V.H., University of Connecticut Health Center.

  • Conflict of interest statement: B. Psaty serves on the Data and Safety Monitoring Board for a clinical trial funded by the manufacturer (Zoll LifeCor) and the Steering Committee of the Yale Open Data Access project funded by Johnson & Johnson. D.J.M. serves on the scientific advisory board of Metacrine. The other authors report no competing financial interests.

  • Data deposition: The database information reported in this paper has been supplied in Datasets S1 and S2. The gene expression profiling data from the Framingham study used herein are available online in dbGaP (www.ncbi.nlm.nih.gov/gap; accession no. phs000007). The full meta-analysis data for the continuous and dichotomous alcohol consumption traits are available online at the dbGaP CHARGE Summary site (accession no. phs000930).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1611243113/-/DCSupplemental.

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β-Klotho, FGF21, and alcohol drinking
Gunter Schumann, Chunyu Liu, Paul O’Reilly, He Gao, Parkyong Song, Bing Xu, Barbara Ruggeri, Najaf Amin, Tianye Jia, Sarah Preis, Marcelo Segura Lepe, Shizuo Akira, Caterina Barbieri, Sebastian Baumeister, Stephane Cauchi, Toni-Kim Clarke, Stefan Enroth, Krista Fischer, Jenni Hällfors, Sarah E. Harris, Saskia Hieber, Edith Hofer, Jouke-Jan Hottenga, Åsa Johansson, Peter K. Joshi, Niina Kaartinen, Jaana Laitinen, Rozenn Lemaitre, Anu Loukola, Jian’an Luan, Leo-Pekka Lyytikäinen, Massimo Mangino, Ani Manichaikul, Hamdi Mbarek, Yuri Milaneschi, Alireza Moayyeri, Kenneth Mukamal, Christopher Nelson, Jennifer Nettleton, Eemil Partinen, Rajesh Rawal, Antonietta Robino, Lynda Rose, Cinzia Sala, Takashi Satoh, Reinhold Schmidt, Katharina Schraut, Robert Scott, Albert Vernon Smith, John M. Starr, Alexander Teumer, Stella Trompet, André G. Uitterlinden, Cristina Venturini, Anne-Claire Vergnaud, Niek Verweij, Veronique Vitart, Dragana Vuckovic, Juho Wedenoja, Loic Yengo, Bing Yu, Weihua Zhang, Jing Hua Zhao, Dorret I. Boomsma, John Chambers, Daniel I. Chasman, Toniolo Daniela, Eco de Geus, Ian Deary, Johan G. Eriksson, Tõnu Esko, Volker Eulenburg, Oscar H. Franco, Philippe Froguel, Christian Gieger, Hans J. Grabe, Vilmundur Gudnason, Ulf Gyllensten, Tamara B. Harris, Anna-Liisa Hartikainen, Andrew C. Heath, Lynne Hocking, Albert Hofman, Cornelia Huth, Marjo-Riitta Jarvelin, J. Wouter Jukema, Jaakko Kaprio, Jaspal S. Kooner, Zoltan Kutalik, Jari Lahti, Claudia Langenberg, Terho Lehtimäki, Yongmei Liu, Pamela A. F. Madden, Nicholas Martin, Alanna Morrison, Brenda Penninx, Nicola Pirastu, Bruce Psaty, Olli Raitakari, Paul Ridker, Richard Rose, Jerome I. Rotter, Nilesh J. Samani, Helena Schmidt, Tim D. Spector, David Stott, David Strachan, Ioanna Tzoulaki, Pim van der Harst, Cornelia M. van Duijn, Pedro Marques-Vidal, Peter Vollenweider, Nicholas J. Wareham, John B. Whitfield, James Wilson, Bruce Wolffenbuttel, Georgy Bakalkin, Evangelos Evangelou, Yun Liu, Kenneth M. Rice, Sylvane Desrivières, Steven A. Kliewer, David J. Mangelsdorf, Christian P. Müller, Daniel Levy, Paul Elliott
Proceedings of the National Academy of Sciences Nov 2016, 201611243; DOI: 10.1073/pnas.1611243113
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Proceedings of the National Academy of Sciences: 118 (16)
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