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

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

doi:10.1073/pnas.1611243113

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

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. HarrisSaskia 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

Research output: Contribution to journal › Article › peer-review

142 Scopus citations

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.

Original language	English (US)
Pages (from-to)	14372-14377
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	50
DOIs	https://doi.org/10.1073/pnas.1611243113
State	Published - Dec 13 2016

Keywords

Alcohol consumption
FGF21
Human
Mouse model
β-Klotho

ASJC Scopus subject areas

General

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10.1073/pnas.1611243113

Cite this

Schumann, G., Liu, C., O'Reilly, P., Gao, H., Song, P., Xu, B., Ruggeri, B., Amin, N., Jia, T., Preis, S., Lepe, M. S., Akira, S., Barbieri, C., Baumeister, S., Cauchi, S., Clarke, T. K., Enroth, S., Fischer, K., Hällfors, J., ... Elliott, P. (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), 14372-14377. https://doi.org/10.1073/pnas.1611243113

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. / Schumann, Gunter; Liu, Chunyu; O'Reilly, Paul et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 50, 13.12.2016, p. 14372-14377.

Research output: Contribution to journal › Article › peer-review

Schumann, G, Liu, C, O'Reilly, P, Gao, H, Song, P, Xu, B, Ruggeri, B, Amin, N, Jia, T, Preis, S, Lepe, MS, Akira, S, Barbieri, C, Baumeister, S, Cauchi, S, Clarke, TK, Enroth, S, Fischer, K, Hällfors, J, Harris, SE, Hieber, S, Hofer, E, Hottenga, JJ, Johansson, Å, Joshi, PK, Kaartinen, N, Laitinen, J, Lemaitre, R, Loukola, A, Luan, J, Lyytikäinen, LP, 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, AC, 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, AL, Heath, AC, Hocking, L, Hofman, A, Huth, C, Jarvelin, MR, 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, Liu, Y, Rice, KM, Desrivières, S, Kliewer, SA , Mangelsdorf, DJ, Müller, CP, Levy, D & Elliott, P 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, vol. 113, no. 50, pp. 14372-14377. https://doi.org/10.1073/pnas.1611243113

@article{c99dbd326f2343b9b98233db157872ae,

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

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.",

keywords = "Alcohol consumption, FGF21, Human, Mouse model, β-Klotho",

author = "Gunter Schumann and Chunyu Liu and Paul O'Reilly and He Gao and Parkyong Song and Bing Xu and Barbara Ruggeri and Najaf Amin and Tianye Jia and Sarah Preis and Lepe, {Marcelo Segura} and Shizuo Akira and Caterina Barbieri and Sebastian Baumeister and Stephane Cauchi and Clarke, {Toni Kim} and Stefan Enroth and Krista Fischer and Jenni H{\"a}llfors and Harris, {Sarah E.} and Saskia Hieber and Edith Hofer and Hottenga, {Jouke Jan} and {\AA}sa Johansson and Joshi, {Peter K.} and Niina Kaartinen and Jaana Laitinen and Rozenn Lemaitre and Anu Loukola and Jian'an Luan and Lyytik{\"a}inen, {Leo Pekka} and Massimo Mangino and Ani Manichaikul and Hamdi Mbarek and Yuri Milaneschi and Alireza Moayyeri and Kenneth Mukamal and Christopher Nelson and Jennifer Nettleton and Eemil Partinen and Rajesh Rawal and Antonietta Robino and Lynda Rose and Cinzia Sala and Takashi Satoh and Reinhold Schmidt and Katharina Schraut and Robert Scott and Smith, {Albert Vernon} and Starr, {John M.} and Alexander Teumer and Stella Trompet and Uitterlinden, {Andr{\'e} G.} and Cristina Venturini and Vergnaud, {Anne Claire} and Niek Verweij and Veronique Vitart and Dragana Vuckovic and Juho Wedenoja and Loic Yengo and Bing Yu and Weihua Zhang and Zhao, {Jing Hua} and Boomsma, {Dorret I.} and John Chambers and Chasman, {Daniel I.} and Toniolo Daniela and {De Geus}, Eco and Ian Deary and Eriksson, {Johan G.} and T{\~o}nu Esko and Volker Eulenburg and Franco, {Oscar H.} and Philippe Froguel and Christian Gieger and Grabe, {Hans J.} and Vilmundur Gudnason and Ulf Gyllensten and Harris, {Tamara B.} and Hartikainen, {Anna Liisa} and Heath, {Andrew C.} and Lynne Hocking and Albert Hofman and Cornelia Huth and Jarvelin, {Marjo Riitta} and Jukema, {J. Wouter} and Jaakko Kaprio and Kooner, {Jaspal S.} and Zoltan Kutalik and Jari Lahti and Claudia Langenberg and Terho Lehtim{\"a}ki and Yongmei Liu and Madden, {Pamela A F} and Nicholas Martin and Alanna Morrison and Brenda Penninx and Nicola Pirastu and Bruce Psaty and Olli Raitakari and Paul Ridker and Richard Rose and Rotter, {Jerome I.} and Samani, {Nilesh J.} and Helena Schmidt and Spector, {Tim D.} and David Stott and David Strachan and Ioanna Tzoulaki and {Van Der Harst}, Pim and {Van Duijn}, {Cornelia M.} and Pedro Marques-Vidal and Peter Vollenweider and Wareham, {Nicholas J.} and Whitfield, {John B.} and James Wilson and Bruce Wolffenbuttel and Georgy Bakalkin and Evangelos Evangelou and Yun Liu and Rice, {Kenneth M.} and Sylvane Desrivi{\`e}res and Kliewer, {Steven A.} and Mangelsdorf, {David J.} and M{\"u}ller, {Christian P.} and Daniel Levy and Paul Elliott",

note = "Funding Information: 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. Funding sources and acknowledgments for contributing authors and consortia can be found in SI Appendix. Part of this work used computing resources provided by Medical Research Council-funded UK Medical Bioinformatics Partnership Programme MR/L01632X/1.",

year = "2016",

month = dec,

day = "13",

doi = "10.1073/pnas.1611243113",

language = "English (US)",

volume = "113",

pages = "14372--14377",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "50",

}

TY - JOUR

T1 - KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

AU - Schumann, Gunter

AU - Liu, Chunyu

AU - O'Reilly, Paul

AU - Gao, He

AU - Song, Parkyong

AU - Xu, Bing

AU - Ruggeri, Barbara

AU - Amin, Najaf

AU - Jia, Tianye

AU - Preis, Sarah

AU - Lepe, Marcelo Segura

AU - Akira, Shizuo

AU - Barbieri, Caterina

AU - Baumeister, Sebastian

AU - Cauchi, Stephane

AU - Clarke, Toni Kim

AU - Enroth, Stefan

AU - Fischer, Krista

AU - Hällfors, Jenni

AU - Harris, Sarah E.

AU - Hieber, Saskia

AU - Hofer, Edith

AU - Hottenga, Jouke Jan

AU - Johansson, Åsa

AU - Joshi, Peter K.

AU - Kaartinen, Niina

AU - Laitinen, Jaana

AU - Lemaitre, Rozenn

AU - Loukola, Anu

AU - Luan, Jian'an

AU - Lyytikäinen, Leo Pekka

AU - Mangino, Massimo

AU - Manichaikul, Ani

AU - Mbarek, Hamdi

AU - Milaneschi, Yuri

AU - Moayyeri, Alireza

AU - Mukamal, Kenneth

AU - Nelson, Christopher

AU - Nettleton, Jennifer

AU - Partinen, Eemil

AU - Rawal, Rajesh

AU - Robino, Antonietta

AU - Rose, Lynda

AU - Sala, Cinzia

AU - Satoh, Takashi

AU - Schmidt, Reinhold

AU - Schraut, Katharina

AU - Scott, Robert

AU - Smith, Albert Vernon

AU - Starr, John M.

AU - Teumer, Alexander

AU - Trompet, Stella

AU - Uitterlinden, André G.

AU - Venturini, Cristina

AU - Vergnaud, Anne Claire

AU - Verweij, Niek

AU - Vitart, Veronique

AU - Vuckovic, Dragana

AU - Wedenoja, Juho

AU - Yengo, Loic

AU - Yu, Bing

AU - Zhang, Weihua

AU - Zhao, Jing Hua

AU - Boomsma, Dorret I.

AU - Chambers, John

AU - Chasman, Daniel I.

AU - Daniela, Toniolo

AU - De Geus, Eco

AU - Deary, Ian

AU - Eriksson, Johan G.

AU - Esko, Tõnu

AU - Eulenburg, Volker

AU - Franco, Oscar H.

AU - Froguel, Philippe

AU - Gieger, Christian

AU - Grabe, Hans J.

AU - Gudnason, Vilmundur

AU - Gyllensten, Ulf

AU - Harris, Tamara B.

AU - Hartikainen, Anna Liisa

AU - Heath, Andrew C.

AU - Hocking, Lynne

AU - Hofman, Albert

AU - Huth, Cornelia

AU - Jarvelin, Marjo Riitta

AU - Jukema, J. Wouter

AU - Kaprio, Jaakko

AU - Kooner, Jaspal S.

AU - Kutalik, Zoltan

AU - Lahti, Jari

AU - Langenberg, Claudia

AU - Lehtimäki, Terho

AU - Liu, Yongmei

AU - Madden, Pamela A F

AU - Martin, Nicholas

AU - Morrison, Alanna

AU - Penninx, Brenda

AU - Pirastu, Nicola

AU - Psaty, Bruce

AU - Raitakari, Olli

AU - Ridker, Paul

AU - Rose, Richard

AU - Rotter, Jerome I.

AU - Samani, Nilesh J.

AU - Schmidt, Helena

AU - Spector, Tim D.

AU - Stott, David

AU - Strachan, David

AU - Tzoulaki, Ioanna

AU - Van Der Harst, Pim

AU - Van Duijn, Cornelia M.

AU - Marques-Vidal, Pedro

AU - Vollenweider, Peter

AU - Wareham, Nicholas J.

AU - Whitfield, John B.

AU - Wilson, James

AU - Wolffenbuttel, Bruce

AU - Bakalkin, Georgy

AU - Evangelou, Evangelos

AU - Liu, Yun

AU - Rice, Kenneth M.

AU - Desrivières, Sylvane

AU - Kliewer, Steven A.

AU - Mangelsdorf, David J.

AU - Müller, Christian P.

AU - Levy, Daniel

AU - Elliott, Paul

N1 - Funding Information: 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. Funding sources and acknowledgments for contributing authors and consortia can be found in SI Appendix. Part of this work used computing resources provided by Medical Research Council-funded UK Medical Bioinformatics Partnership Programme MR/L01632X/1.

PY - 2016/12/13

Y1 - 2016/12/13

N2 - 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.

AB - 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.

KW - Alcohol consumption

KW - FGF21

KW - Human

KW - Mouse model

KW - β-Klotho

UR - http://www.scopus.com/inward/record.url?scp=85006055058&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006055058&partnerID=8YFLogxK

U2 - 10.1073/pnas.1611243113

DO - 10.1073/pnas.1611243113

M3 - Article

C2 - 27911795

AN - SCOPUS:85006055058

VL - 113

SP - 14372

EP - 14377

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 50

ER -

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

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