KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.
Gunter SchumannChunyu LiuPaul O'ReillyHe GaoParkyong SongBing XuBarbara RuggeriNajaf AminTianye JiaSarah PreisMarcelo Segura LepeShizuo AkiraCaterina BarbieriSebastian BaumeisterStephane CauchiToni-Kim ClarkeStefan EnrothKrista FischerJenni HällforsSarah E HarrisSaskia HieberEdith HoferJouke-Jan HottengaÅsa JohanssonPeter K JoshiNiina KaartinenJaana LaitinenRozenn LemaitreAnu LoukolaJian'an LuanLeo-Pekka LyytikäinenMassimo ManginoAni ManichaikulHamdi MbarekYuri MilaneschiAlireza MoayyeriKenneth MukamalChristopher NelsonJennifer NettletonEemil PartinenRajesh RawalAntonietta RobinoLynda RoseCinzia SalaTakashi SatohReinhold SchmidtKatharina SchrautRobert ScottAlbert Vernon SmithJohn M StarrAlexander TeumerStella TrompetAndré G UitterlindenCristina VenturiniAnne-Claire VergnaudNiek VerweijVeronique VitartDragana VuckovicJuho WedenojaLoic YengoBing YuWeihua ZhangJing Hua ZhaoDorret I BoomsmaJohn ChambersDaniel I ChasmanToniolo DanielaEco de GeusIan DearyJohan G ErikssonTõnu EskoVolker EulenburgOscar H FrancoPhilippe FroguelChristian GiegerHans J GrabeVilmundur GudnasonUlf GyllenstenTamara B HarrisAnna-Liisa HartikainenAndrew C HeathLynne HockingAlbert HofmanCornelia HuthMarjo-Riitta JarvelinJ Wouter JukemaJaakko KaprioJaspal S KoonerZoltan KutalikJari LahtiClaudia LangenbergTerho LehtimäkiYongmei LiuPamela A F MaddenNicholas MartinAlanna MorrisonBrenda PenninxNicola PirastuBruce PsatyOlli RaitakariPaul RidkerRichard RoseJerome I RotterNilesh J SamaniHelena SchmidtTim D SpectorDavid StottDavid StrachanIoanna TzoulakiPim van der HarstCornelia M van DuijnPedro Marques-VidalPeter VollenweiderNicholas J WarehamJohn B WhitfieldJames WilsonBruce WolffenbuttelGeorgy BakalkinEvangelos EvangelouYun LiuKenneth M RiceSylvane DesrivièresSteven A KliewerDavid J MangelsdorfChristian P MüllerDaniel LevyPaul ElliottPublished in: Proceedings of the National Academy of Sciences of the United States of America (2016)
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.