The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference
Open accessAbstract
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.
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In the citing paper
“Genome-wide, genetic correlations were significantly < 1 with log-scaled alcohol consumption by participants in AlcGen and CHARGE+ Consortia cohorts16 (rg = 0.695) and in the UK Biobank17 (rg = 0.371).”
From Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders (2018) · cites this paper as [16]
The cited source says what the claim attributes to it.
In the citing paper
“several recent studies confirmed that hepatic FGF21 increases in response to other nutritional stimuli, including conditions of macronutrient imbalance [152], and in response to alcohol intake [138,140,153].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [140]
In the citing paper
“AD was genetically correlated with alcohol consumption in a meta-analysis of the Alcohol Genome-wide Association (AlcGen) and Cohorts for Aging and Research in Genomic Epidemiology Plus (CHARGE+) consortia16 (rg = 0.695, SE = 0.155, p = 6.9E-6)”
From Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders (2018) · cites this paper as [16]
In the citing paper
“They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6–11.”
From Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use (2019) · cites this paper as [10]
In the citing paper
“Similarly to its regulation of nutrient homeostasis, FGF21 production by the liver is also increased in response to alcohol intake132,133, and administration of FGF21 suppresses alcohol intake122,134.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [134]
In the citing paper
“Finally, as would be predicted from the human SNP data, Klbfl/fl;CamK2a-Cre mice consume more alcohol and prefer alcohol more than wild-type control mice (116).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [116]
In the citing paper
“FGF21 also regulates alcohol intake.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [116]
In the citing paper
“Interestingly, administering recombinant FGF21 (116) or the overexpression of FGF21 (125) significantly reduced alcohol preference but not plasma ethanol concentrations.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [116]
In the citing paper
“and the rs11940694 SNP in the β-Klotho (KLB) locus associates with alcohol consumption (116).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [116]
In the citing paper
“This effect of FGF21 is lost is mice lacking β-klotho in the central nervous system (CNS; Klbfl/fl;CamK2a-Cre) (116).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [116]
In the citing paper
“Similar linkages have also been found in the FGF21 co-receptor Klb, although these associations have primarily focused on alcohol intake”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [176]
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Citations
Cites
LD Score regression distinguishes confounding from polygenicity in genome-wide association studies
Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bulik-Sullivan, B. K., Loh, P.-R., Finucane, H. K., Ripke, S., Yang, J., Patterson, N., Daly, M. J., Price, A. L., & Neale, B. M. (2015) · Nature Genetics · doi:10.1038/ng.3211 · Cited by 5,559
METAL: fast and efficient meta-analysis of genomewide association scans
Willer, C. J., Li, Y., & Abecasis, G. R. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq340 · Cited by 5,205
Rehm, J., Mathers, C., Popova, S., Thavorncharoensap, M., Teerawattananon, Y., & Patra, J. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60746-7 · Cited by 3,870
Strategy of prevention: lessons from cardiovascular disease.
Rose, G. (1981) · BMJ · doi:10.1136/bmj.282.6279.1847 · Cited by 1,302
Understanding the Physiology of FGF21
Fisher, F. M., & Maratos-Flier, E. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105339 · Cited by 912
Splansky, G. L., Corey, D., Yang, Q., Atwood, L. D., Cupples, L. A., Benjamin, E. J., D'Agostino, R. B., Fox, C. S., Larson, M. G., Murabito, J. M., et al. (2007) · American Journal of Epidemiology · doi:10.1093/aje/kwm021 · Cited by 860
Self-citationFGF21 regulates metabolism and circadian behavior by acting on the nervous system
Bookout, A. L., de Groot, M. H. M., Owen, B. M., Lee, S., Gautron, L., Lawrence, H. L., Ding, X., Elmquist, J. K., Takahashi, J. S., Mangelsdorf, D. J., et al. (2013) · Nature Medicine · doi:10.1038/nm.3249 · Cited by 545
Self-citationFGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss
Owen, B. M., Ding, X., Morgan, D. A., Coate, K. C., Bookout, A. L., Rahmouni, K., Kliewer, S. A., & Mangelsdorf, D. J. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.012 · Cited by 523
A key role for corticotropin-releasing factor in alcohol dependence
Heilig, M., & Koob, G. F. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.06.006 · Cited by 503 · cited 1×
“Among its actions in the hypothalamus, FGF21 induces corticotropin-releasing hormone (18, 19), which is a strong modulator of alcohol consumption (23).”
FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver
von Holstein-Rathlou, S., BonDurant, L. D., Peltekian, L., Naber, M. C., Yin, T. C., Claflin, K. E., Urizar, A. I., Madsen, A. N., Ratner, C., Holst, B., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.003 · Cited by 347
Research works printed but not linked: 1
- Anonymous Global Status Report on Alcohol and Health (WHO, Geneva, 2014).
Cited by
Sorted by citations
23andMe Research Team, Liu, M., Psychiatry, H. A.-I., Jiang, Y., Wedow, R., Li, Y., Brazel, D. M., Chen, F., Datta, G., Davila-Velderrain, J., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0307-5 · Cited by 1,896
Self-citationDavies, G., Lam, M., Harris, S. E., Trampush, J. W., Luciano, M., Hill, W. D., Hagenaars, S. P., Ritchie, S. J., Marioni, R. E., Fawns‐Ritchie, C., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04362-x · Cited by 686
Self-citationCarvalho, A. F., Heilig, M. A., Perez, A., Probst, C., & Rehm, J. T. (2019) · The Lancet · doi:10.1016/s0140-6736(19)31775-1 · Cited by 714
23andMe Research Team, Walters, R. K., Polimanti, R., Johnson, E. C., McClintick, J. N., Adams, M. J., Adkins, A. E., Aliev, F., Bacanu, S.-A., Batzler, A., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0275-1 · Cited by 632
Self-citationKranzler, H. R., Zhou, H., Kember, R. L., Vickers‐Smith, R., Justice, A. C., Damrauer, S. M., Tsao, P. S., Klarin, D. M., Baras, A., Reid, J. G., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09480-8 · Cited by 482
Metadata
- 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., 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., & Elliott, P.
- Affiliations
- Medical Research Council—Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8AF, United Kingdom;
- Boston University (US)
- King's College London (GB)
- Public Health England (GB)
- Howard Hughes Medical Institute (US)
- Erasmus MC (NL)
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, United Kingdom;
- Immunology Frontier Research Center, The University of Osaka (JP)
- IRCCS Ospedale San Raffaele (IT)
- Universitätsmedizin Greifswald (DE)
- CNRS UMR 8199, Lille Pasteur Institute, European Genomic Institute for Diabetes, Lille 2 University, 59000 Lille, France;
- University of Edinburgh (GB)
- Uppsala University (SE)
- University of Tartu (EE)
- University of Helsinki (FI)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Medical University of Graz (AT)
- Amsterdam Public Health (NL)
- Finnish Institute for Health and Welfare (FI)
- Finnish Institute of Occupational Health (FI)
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101;
- University of Cambridge (GB)
- Tampere University (FI)
- Beth Israel Deaconess Medical Center (US)
- University of Leicester (GB)
- Brigham and Women's Hospital (US)
- Alzheimer Scotland (GB)
- University Medical Center Groningen (NL)
- Medical Research Council Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom;
- University of Trieste (IT)
- National Health Service (GB)
- Division of Genetics and Cell Biology, San Raffaele Research Institute, 20132 Milan, Italy;
- Department of Biological Psychology, Vrije Universiteit Amsterdam and EMGO Institute for Health and Care Research, 1081 BT Amsterdam, The Netherlands;
- Centre National de la Recherche Scientifique (FR)
- University of Iceland (IS)
- National Institutes of Health (US)
- Washington University in St. Louis (US)
- University of Aberdeen (GB)
- Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands;
- Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudoise, 1010 Lausanne, Switzerland;
- Shanghai Medical College of Fudan University (CN)
- QIMR Berghofer Medical Research Institute (AU)
- Group Health Cooperative (US)
- University of Turku (FI)
- University of California, Los Angeles (US)
- St George's, University of London (GB)
- University of Ioannina (GR)
- Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands;
- Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands;
- Department of Medicine, Internal Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland;
- Western General Hospital (GB)
- University of Washington (US)
- ORCID
- Liu, Chunyu
- O’Reilly, Paul
- Gao, He
- Song, Parkyong
- Xu, Bing
- Ruggeri, Barbara
- Amin, Najaf
- Jia, Tianye
- Preis, Sarah
- Akira, Shizuo
- Barbieri, Caterina
- Baumeister, Sebastian
- Clarke, Toni-Kim
- Enroth, Stefan
- Fischer, Krista
- Hällfors, Jenni
- Harris, Sarah E.
- Hieber, Saskia
- Hofer, Edith
- Hottenga, Jouke-Jan
- Johansson, Åsa
- Joshi, Peter K.
- Kaartinen, Niina
- Laitinen, Jaana
- Loukola, Anu
- Luan, Jian’an
- Lyytikäinen, Leo-Pekka
- Mangino, Massimo
- Manichaikul, Ani
- Mbarek, Hamdi
- Milaneschi, Yuri
- Moayyeri, Alireza
- Mukamal, Kenneth
- Partinen, Eemil
- Rawal, Rajesh
- Robino, Antonietta
- Rose, Lynda
- Sala, Cinzia
- Satoh, Takashi
- Schmidt, Reinhold
- Smith, Albert Vernon
- Starr, John M.
- Teumer, Alexander
- Trompet, Stella
- Uitterlinden, André G.
- Venturini, Cristina
- Verweij, Niek
- Vuckovic, Dragana
- Wedenoja, Juho
- Yu, Bing
- Zhang, Weihua
- Zhao, Jing Hua
- Boomsma, Dorret I.
- Chambers, John
- Chasman, Daniel I.
- Deary, Ian
- Eriksson, Johan G.
- Esko, Tõnu
- Eulenburg, Volker
- Franco, Oscar H.
- Froguel, Philippe
- Gieger, Christian
- Grabe, Hans J.
- Gudnason, Vilmundur
- Gyllensten, Ulf
- Harris, Tamara B.
- Heath, Andrew C.
- Hocking, Lynne
- Huth, Cornelia
- Jukema, J. Wouter
- Kaprio, Jaakko
- Kooner, Jaspal S.
- Lahti, Jari
- Langenberg, Claudia
- Lehtimäki, Terho
- Madden, Pamela A. F.
- Martin, Nicholas
- Morrison, Alanna
- Penninx, Brenda
- Pirastu, Nicola
- Psaty, Bruce
- Raitakari, Olli
- Ridker, Paul
- Rose, Richard
- Rotter, Jerome I.
- Samani, Nilesh J.
- Schmidt, Helena
- Spector, Tim D.
- Stott, David
- Strachan, David
- Tzoulaki, Ioanna
- Marques-Vidal, Pedro
- Wareham, Nicholas J.
- Whitfield, John B.
- Wilson, James
- Wolffenbuttel, Bruce
- Bakalkin, Georgy
- Liu, Yun
- Rice, Kenneth M.
- Desrivières, Sylvane
- Kliewer, Steven A.
- Mangelsdorf, David J.
- Müller, Christian P.
- Levy, Daniel
- Elliott, Paul
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-11-28
- Volume
- 113
- Issue
- 50
- Pages
- 14372-14377
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5167198
- OpenAlex
- W2559170486
- Cited by
- 241
- References
- 25
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 20 · 2023: 23 · 2022: 18 · 2021: 29 · 2020: 30 · 2019: 34 · 2018: 37 · 2017: 20 · 2016: 1
- FWCI
- 15.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- VU Research Portal (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion)
- IRIS (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Apollo
- WOS
- Funders
- National Science Foundation
- GlaxoSmithKline
- National Institute for Health and Care Research (NF-SI-0507-10228, NF-SI-0611-10136, NF-SI-0514-10027, NF-SI-0512-10135)
- European Commission
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Svenska Forskningsrådet Formas
- Bundesministerium für Bildung und Forschung
- Fondation Leenaards
- Forskningsrådet om Hälsa, Arbetsliv och Välfärd
- National Institutes of Health (1r01hl120393-01a1, UL1TR000124)
- Medical Research Council (MR/L01632X/1, MR/N01104X/1, MR/L01341X/1, MR/K026992/1, MR/N015746/1, MC_UU_12015/1, MR/N000390/1)
- National Health and Medical Research Council
- National Institute on Alcohol Abuse and Alcoholism (R01AA012502)
- National Heart, Lung, and Blood Institute (R01-HL120393, U01HL130114, R01HL105756)
- National Institute of Mental Health
- National Cancer Institute (UM1CA182913)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- alcohol consumption, alcohol preference, β-Klotho, FGF21, FGF19, FGF signaling, brain, genetic susceptibility, alcoholism
- MeSH terms
- Klotho Proteins, Alcohol Drinking, Animals, Behavior, Animal, Brain, Emotions, Female, Fibroblast Growth Factors, Humans, Liver, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Polymorphism, Single Nucleotide, Mice, Genome-Wide Association Study, Mice, 129 Strain
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