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 |
|---|---|
| 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 | |
| Publication status | Published - 13 Dec 2016 |
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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; Segura Lepe, Marcelo; 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 › Academic › 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 - Segura Lepe, Marcelo
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 - Journal Article
U2 - 10.1073/pnas.1611243113
DO - 10.1073/pnas.1611243113
M3 - Article
C2 - 27911795
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 -