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 | |
| State | Published - Dec 13 2016 |
Keywords
- Alcohol consumption
- FGF21
- Human
- Mouse model
- β-Klotho
ASJC Scopus subject areas
- General
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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 journal › Article › peer-review
}
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 -