Gunter Schumann^a,1,2, Chunyu Liu^b,c,d,1, Paul O’Reilly^a,1, He Gao^e,f,1, Parkyong Song^g,h,1, Bing Xu^a, Barbara Ruggeri^a, Najaf Aminⁱ, Tianye Jia^a, Sarah Preis^d, Marcelo Segura Lepe^e,j, Shizuo Akira^k, Caterina Barbieri^l, Sebastian Baumeister^m,n, Stephane Cauchi^o, Toni-Kim Clarke^p, Stefan Enroth^q, Krista Fischer^r, Jenni Hallfors^s, Sarah E. Harris^t,u, Saskia Hieber^v, Edith Hofer^w,x, Jouke-Jan Hottenga^y, Asa Johansson^q, Peter K. Joshi^z, Niina Kaartinen^aa, Jaana Laitinen^bb, Rozenn Lemaitre^cc, Anu Loukolas,^dd, Jian’an Luan^ee, Leo-Pekka Lyytikainen^ff, Massimo Manginogg,^hh, Ani Manichaikulii,^jj, Hamdi Mbarek^y, Yuri Milaneschi^kk, Alireza Moayyeri^e,ll,mm, Kenneth Mukamalⁿⁿ, Christopher Nelson^oo,pp, Jennifer Nettleton^qq, Eemil Partinen^rr, Rajesh Rawal^ss, Antonietta Robino^tt, Lynda Rose^uu, Cinzia Sala^l, Takashi Satoh^k, Reinhold Schmidt^w, Katharina Schraut^z, Robert Scott^vv, Albert Vernon Smith^ww, John M. Starr^t,xx, Alexander Teumer^m,yy, Stella Trompet^zz,aaa, Andre G. Uitterlinden^bbb,ccc, Cristina Venturini^gg, Anne-Claire Vergnaud^e,  Niek Verweij^ddd,  Veronique Vitart^eee, Dragana Vuckovic^fff, Juho Wedenoja^dd, Loic Yengo^o, Bing Yu^ggg,hhh, Weihua Zhang^e,iii, Jing Hua Zhao^vv, Dorret I. Boomsma^y, John hambers^e,iii,jjj, Daniel I. Chasman^uu,kkk, Toniolo Daniela^l, Eco de Geus^y, Ian Deary^t,lll, Johan G. Eriksson^aa,mmm,nnn,ooo,ppp, Tonu Esko^r, Volker Eulenbur^gqqq, Oscar H. Franco^ccc, Philippe Froguel^o,rrr, Christian Gieger^ss, Hans J. Grabe^sss, Vilmundur Gudnason^ww,ttt, Ulf Gyllensten^q, Tamara B. Harris^uuu, Anna-Liisa Hartikainenv^vv,www,xxx, Andrew C. Heathy^yy, Lynne Hocking^zzz, Albert Hofman^ccc, Cornelia Huth^aaaa, Marjo-Riitta Jarvelin^{e,xxx,bbbb,cccc}, J. Wouter Jukem^azz, Jaakko Kaprio^s,aa,dd, Jaspal S. Koone^{riii,jjj,dddd}, Zoltan Kutalik^eeee, Jari Lahti^{ooo,ffff,gggg}, Claudia Langenberg^ee, Terho Lehtimaki^ff, Yongmei Liu^hhhh, Pamela A. F. Maddenⁱⁱⁱⁱ, Nicholas Martin^jjjj, Alanna Morrison^ggg, Brenda Penninx^kk, Nicola Pirastu^z,fff, Bruce Psaty^{cc,kkkk,llll,mmmm}, Olli Raitakari^nnnn,oooo, Paul Ridker^uu,kkk, Richard Rose^pppp, Jerome I. Rotter^qqqq, Nilesh J. Samani^oo,pp, Helena Schmidtr^rrr, Tim D. Spector^gg, David Stott^ssss, David Strachan^tttt, Ioanna Tzoulaki^e,f,uuuu, Pim van der Harst^{ddd,vvvv,wwww}, Cornelia M. van Duijnⁱ, Pedro Marques-Vidal^xxxx, Peter Vollenweider^xxxx, Nicholas J. Wareham^vv, John B. Whitfield^jjjj, James Wilsonz,^eee, Bruce Wolffenbuttel^yyyy, Georgy Bakalkin^zzzz, Evangelos Evangelou^e,uuuu, Yun Liu^aaaaa,bbbbb, Kenneth M. Rice^ccccc, Sylvane Desrivieres^a,1, Steven A. Kliewer^g,ddddd,1, David J. Mangelsdorf^g,h,1,2, Christian P. Muller^v,1, Daniel Levy^b,c,1, and Paul Elliott<sup>e,f,1,2

a</sup>Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8AF, United Kingdom;
^bThe Framingham Heart Study, Framingham, MA 01702;
^cThe Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD 20824;
^dDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118;
^eDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom;
^fMedical Research Council-Public Health England Centre for Environment and Health, Imperial College London, London W2 1PG, United Kingdom;
^gDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
^hHoward Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390;
ⁱGenetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands;
^jSection of Bioinformatics, Bayer Pharma AG, 13342 Berlin, Germany;
^kLaboratory of Host Defense, World Premier International Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;
^lDivision of Genetics and Cell Biology, San Raffaele Research Institute, 20132 Milan, Italy;
^mInstitute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany;
ⁿDepartment of Epidemiology and Preventive Medicine, University of Regensburg, 93053 Regensburg, Germany;
^oCNRS UMR 8199, Lille Pasteur Institute, European Genomic Institute for Diabetes, Lille 2 University, 59000 Lille, France;
^pDivison of Psychiatry, University of Edinburgh, Edinburgh EH10 5HF, United Kingdom;
^qScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 75108 Uppsala, Sweden;
^rEstonian Genome Center, University of Tartu, 51010 Tartu, Estonia;
^sInstitute for Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland;
^tCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom;
^uCentre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;
^vDepartment of Psychiatry and Psychotherapy, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany;
^wClinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, 8036 Graz, Austria;
^xInstitute of Medical Informatics, Statistics and Documentation, Medical University Graz, 8036 Graz, Austria;
^yDepartment of Biological Psychology, Vrije Universiteit Amsterdam and EMGO Institute for Health and Care Research, 1081 BT Amsterdam, The Netherlands;
^zUsher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom;
^aaNational Institute for Health and Welfare, 00271 Helsinki, Finland;
^bbQuantified Employee-Unit, Finnish Institute of Occupational Health, 00250 Helsinki, Finland;
^ccCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101;
^ddDepartment of Public Health, University of Helsinki, 00014 Helsinki, Finland;
^eeMedical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom;
^ffDepartment of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland;
^ggDepartment of Twin Research and Genetic Epidemiology, King’s College, London SE1 7EH, United Kingdom;
^hhNational Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ Foundation Trust, London SE1 9RT, United Kingdom;
ⁱⁱCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22903;
^jjBiostatistics Section, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22903;
^kkDepartment of Psychiatry, Institute for Health and Care Research (EMGO) Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit Amsterdam University Medical Center/Geestelijke Gezondheids Zorg (GGZ) inGeest, 1081 HL Amsterdam, The Netherlands;
^llInstitute of Health Informatics, University College London, London NW1 2DA, United Kingdom;
^mmFarr Institute of Health Informatics Research, University College London Institute of Health Informatics, London NW1 2DA, United Kingdom;
ⁿⁿDepartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
^ooDepartment of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom;
^ppNational Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, United Kingdom;
^qqDivision of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Sciences Center, Houston, TX 77225;
^rrFaculty of Medicine, University of Tartu, 50411 Tartu, Estonia;
^ssDepartment of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Munchen, 85764 Neuherberg, Germany;
^ttInstitute for Maternal and Child Health?Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Burlo Garofolo, 34137 Trieste, Italy;
^uuDivision of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA 02215;
^vvMedical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom;
^wwResearch Institute, Icelandic Heart Association, 201 Kopavogur, Iceland;
^xxAlzheimer Scotland Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom;
^yyInterfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany;
^zzDepartment of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
^aaaDepartment of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
^bbbDepartment of internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands;
^cccDepartment of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands;
^dddDepartment of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands;
^eeeMedical Research Council Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom;
^fffDepartment of Medical Sciences, University of Trieste, 34149 Trieste, Italy;
^gggHuman Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77225;
^hhhDivision of Epidemiology, University of Texas Health Science Center at Houston, Houston, TX 77225;
ⁱⁱⁱDepartment of Cardiology, Ealing Hospital, Middlesex UB1 3HW, United Kingdom;
^jjjImperial College Healthcare National Health Service Trust, London W12 0HS, United Kingdom;
^kkkHarvard Medical School, Boston, MA 02115;
^lllPsychology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom;
^mmmDepartment of General Practice and Primary Health Care, University of Helsinki, 00014 Helsinki, Finland;
ⁿⁿⁿUnit of General Practice, Helsinki University Central Hospital, 00014 Helsinki, Finland;
^oooFolkhalsan Research Centre, Public Health Research, 00290 Helsinki, Finland;
^pppVasa Central Hospital, 65130 Vasa, Finland;
^qqqInstitute for Biochemistry and Molecular Medicine, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany;
^rrrDepartment of Genomics of Common Disease, School of Public Health, Imperial College London, London W12 0HR, United Kingdom;
^sssDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany;
^tttFaculty of Medicine, University of Iceland, 101 Reykjavik, Iceland;
^uuuNational Institute on Aging, NIH, Bethesda, MD 20892;
^vvvDepartment of Obstetrics and Gynecology, Oulu University Hospital, 90029 Oulu, Finland;
^wwwMedical Research Center, University of Oulu, 90014 Oulu, Finland;
^xxxUnit of Primary Care, Oulu University Hospital, 90220 Oulu, Finland;
^yyyDepartment of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110;
^zzzInstitute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom;
^aaaaInstitute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health GmbH, D-85764 Neuherberg, Germany;
^bbbbCenter for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu FI-90014, Finland;
^ccccBiocenter Oulu, University of Oulu, Oulu FI-90014, Finland;
^ddddFaculty of Medicine, National Heart & Lung Institute, Cardiovascular Science, Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom;
^eeeeInstitute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudoise, 1010 Lausanne, Switzerland;
^ffffCollegium for Advanced Studies, University of Helsinki, 00014 Helsinki, Finland;
^ggggInstitute of Behavioural Sciences, University of Helsinki, 00014 Helsinki, Finland;
^hhhhWake Forest School of Medicine, Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157;
ⁱⁱⁱⁱDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110;
^jjjjGenetic Epidemiology, Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Brisbane QLD 4029, Australia;
^kkkkDepartment of Epidemiology, University of Washington, Seattle, WA 98195;
^llllDepartment of Health Services, University of Washington, Seattle, WA 98195;
^mmmmGroup Health Cooperative, Group Health Research Institute, Seattle, WA 98101;
ⁿⁿⁿⁿDepartment of Clinical Physiology and Nuclear Medicine, Turku University Hospital, University of Turku, Turku 20520, Finland;
^ooooResearch Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland;
^ppppDepartment of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405;
^qqqqInstitute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor?University of California, Los Angeles Medical Center, Torrance, CA 90509;
^rrrrInstitute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, 8010 Graz, Austria;
^ssssInstitute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G31 2ER, United Kingdom;
^ttttPopulation Health Research Institute, St. George's, University of London, London SW17 0RE, United Kingdom;
^uuuuDepartment of Hygiene and Epidemiology, University of Ioannina Medical School, 45110 Ioannina, Greece;
^vvvvDepartment of Genetics, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands;
^wwwwDurrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of The Netherlands?Netherlands Heart Institute, 3511GC Utrecht, The Netherlands;
^xxxxDepartment of Medicine, Internal Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland;
^yyyyDepartment of Endocrinology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands;
^zzzzDivision of Biological Research on Drug Dependence, Department of Pharmaceutical, Biosciences, Uppsala University, 751 24 Uppsala, Sweden;
aaaaaKey Laboratory of Metabolism and Molecular Medicine, Ministry of Education, 200032 Shanghai, People’s Republic of China;
^bbbbbDepartment of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, 200032 Shanghai, People’s Republic of China;
^cccccDepartment of Biostatistics, University of Washington, Seattle, WA 98195;
^dddddDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390

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.

alcohol consumption, human, β-Klotho, FGF21, mouse model

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.

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.