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 & 107 others 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

Research output: Contribution to journalArticle

64 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)14372-14377
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number50
DOIs
StatePublished - Dec 13 2016

Fingerprint

Alcohol Drinking
Alcohols
Genes
Brain
Drinking Behavior
Liver
Drinking
Habits
fibroblast growth factor 21
Public Health
Genome
Hormones

Keywords

  • Alcohol consumption
  • FGF21
  • Human
  • Mouse model
  • β-Klotho

ASJC Scopus subject areas

  • General

Cite this

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; Gao, He; Song, Parkyong; Xu, Bing; Ruggeri, Barbara; Amin, Najaf; Jia, Tianye; Preis, Sarah; Lepe, Marcelo Segura; Akira, Shizuo; Barbieri, Caterina; Baumeister, Sebastian; Cauchi, Stephane; 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; Lemaitre, Rozenn; Loukola, Anu; Luan, Jian'an; Lyytikäinen, Leo Pekka; Mangino, Massimo; Manichaikul, Ani; Mbarek, Hamdi; Milaneschi, Yuri; Moayyeri, Alireza; Mukamal, Kenneth; Nelson, Christopher; Nettleton, Jennifer; Partinen, Eemil; Rawal, Rajesh; Robino, Antonietta; Rose, Lynda; Sala, Cinzia; Satoh, Takashi; Schmidt, Reinhold; Schraut, Katharina; Scott, Robert; Smith, Albert Vernon; Starr, John M.; Teumer, Alexander; Trompet, Stella; Uitterlinden, André G.; Venturini, Cristina; Vergnaud, Anne Claire; Verweij, Niek; Vitart, Veronique; Vuckovic, Dragana; Wedenoja, Juho; Yengo, Loic; Yu, Bing; Zhang, Weihua; Zhao, Jing Hua; Boomsma, Dorret I.; Chambers, John; Chasman, Daniel I.; Daniela, Toniolo; De Geus, Eco; 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.; Hartikainen, Anna Liisa; Heath, Andrew C.; Hocking, Lynne; Hofman, Albert; Huth, Cornelia; Jarvelin, Marjo Riitta; Jukema, J. Wouter; Kaprio, Jaakko; Kooner, Jaspal S.; Kutalik, Zoltan; Lahti, Jari; Langenberg, Claudia; Lehtimäki, Terho; Liu, Yongmei; 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; Van Der Harst, Pim; Van Duijn, Cornelia M.; Marques-Vidal, Pedro; Vollenweider, Peter; Wareham, Nicholas J.; Whitfield, John B.; Wilson, James; Wolffenbuttel, Bruce; Bakalkin, Georgy; Evangelou, Evangelos; Liu, Yun; Rice, Kenneth M.; Desrivières, Sylvane; Kliewer, Steven A.; Mangelsdorf, David J.; Müller, Christian P.; Levy, Daniel; Elliott, Paul.

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 journalArticle

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
Schumann, Gunter ; Liu, Chunyu ; O'Reilly, Paul ; Gao, He ; Song, Parkyong ; Xu, Bing ; Ruggeri, Barbara ; Amin, Najaf ; Jia, Tianye ; Preis, Sarah ; Lepe, Marcelo Segura ; Akira, Shizuo ; Barbieri, Caterina ; Baumeister, Sebastian ; Cauchi, Stephane ; 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 ; Lemaitre, Rozenn ; Loukola, Anu ; Luan, Jian'an ; Lyytikäinen, Leo Pekka ; Mangino, Massimo ; Manichaikul, Ani ; Mbarek, Hamdi ; Milaneschi, Yuri ; Moayyeri, Alireza ; Mukamal, Kenneth ; Nelson, Christopher ; Nettleton, Jennifer ; Partinen, Eemil ; Rawal, Rajesh ; Robino, Antonietta ; Rose, Lynda ; Sala, Cinzia ; Satoh, Takashi ; Schmidt, Reinhold ; Schraut, Katharina ; Scott, Robert ; Smith, Albert Vernon ; Starr, John M. ; Teumer, Alexander ; Trompet, Stella ; Uitterlinden, André G. ; Venturini, Cristina ; Vergnaud, Anne Claire ; Verweij, Niek ; Vitart, Veronique ; Vuckovic, Dragana ; Wedenoja, Juho ; Yengo, Loic ; Yu, Bing ; Zhang, Weihua ; Zhao, Jing Hua ; Boomsma, Dorret I. ; Chambers, John ; Chasman, Daniel I. ; Daniela, Toniolo ; De Geus, Eco ; 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. ; Hartikainen, Anna Liisa ; Heath, Andrew C. ; Hocking, Lynne ; Hofman, Albert ; Huth, Cornelia ; Jarvelin, Marjo Riitta ; Jukema, J. Wouter ; Kaprio, Jaakko ; Kooner, Jaspal S. ; Kutalik, Zoltan ; Lahti, Jari ; Langenberg, Claudia ; Lehtimäki, Terho ; Liu, Yongmei ; 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 ; Van Der Harst, Pim ; Van Duijn, Cornelia M. ; Marques-Vidal, Pedro ; Vollenweider, Peter ; Wareham, Nicholas J. ; Whitfield, John B. ; Wilson, James ; Wolffenbuttel, Bruce ; Bakalkin, Georgy ; Evangelou, Evangelos ; Liu, Yun ; Rice, Kenneth M. ; Desrivières, Sylvane ; Kliewer, Steven A. ; Mangelsdorf, David J. ; Müller, Christian P. ; Levy, Daniel ; Elliott, Paul. / KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 50. pp. 14372-14377.
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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.",
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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

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

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U2 - 10.1073/pnas.1611243113

DO - 10.1073/pnas.1611243113

M3 - Article

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 -