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

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 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 PA; 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

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

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 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 PA; 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

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

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 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 PA

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

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NATL ACAD SCIENCES

doi:10.1073/pnas.1611243113

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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042716232

Tiivistelmä

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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