Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Niamh MullinsAndreas J ForstnerKevin S O'ConnellBrandon CoombesJonathan R I ColemanZhen QiaoThomas D AlsTim B BigdeliSigrid BørteJulien BryoisAlexander W CharneyOle Kristian DrangeMichael J GandalSaskia P HagenaarsMasashi IkedaNolan KamitakiMinsoo KimKristi KrebsGeorgia PanagiotaropoulouBrian M SchilderLaura G SloofmanStacy SteinbergVassily TrubetskoyBendik S WinsvoldHong-Hee WonLiliya AbramovaKristina AdorjanEsben AgerboMariam Al EissaDiego AlbaniNey Alliey-RodriguezAdebayo AnjorinVerneri AntillaAnastasia AntoniouSwapnil AwasthiJi Hyun BaekMarie Bækvad-HansenNicholas BassMichael BauerEva C BeinsSarah E BergenArmin BirnerCarsten Bøcker PedersenErlend BøenMarco P BoksRosa BoschMurielle BrumBen M BrumptonNathalie Brunkhorst-KanaanMonika BuddeJonas Bybjerg-GrauholmWilliam ByerleyMurray CairnsMiquel CasasPablo CervantesToni-Kim ClarkeCristiana CruceanuAlfredo Cuellar-BarbozaJulie CunninghamDavid CurtisPiotr M CzerskiAnders M DaleNina DalknerFriederike S DavidFranziska DegenhardtSrdjan DjurovicAmanda L DobbynAthanassios DouzenisTorbjørn ElvsåshagenValentina Escott-PriceI Nicol FerrierAlessia FiorentinoTatiana M ForoudLiz FortyJosef FrankOleksandr FreiNelson B FreimerLouise FrisénKatrin GadeJulie GarnhamJoel GelernterMarianne Giørtz PedersenIan R GizerScott D GordonKatherine Gordon-SmithTiffany A GreenwoodJakob GroveJosé Guzman-ParraKyooseob HaMagnus HaraldssonMartin HautzingerUrs HeilbronnerDennis HellgrenStefan HermsPer HoffmannPeter A HolmansLaura HuckinsStéphane JamainJessica S JohnsonJanos L KalmanYoichiro KamataniJames L KennedySarah Kittel-SchneiderJames A KnowlesManolis KogevinasMaria KorominaThorsten M KranzHenry R KranzlerMichiaki KuboRalph KupkaSteven A KushnerCatharina LavebrattJacob LawrenceMarkus LeberHeon-Jeong LeePhil H LeeShawn E LevyCatrin LewisCalwing LiaoSusanne LucaeMartin LundbergDonald J MacIntyreSigurdur H MagnussonWolfgang MaierAdam MaihoferDolores MalaspinaEirini MaratouLina MartinssonManuel MattheisenSteven A McCarrollNathaniel W McGregorPeter McGuffinJames D McKayHelena MedeirosSarah E MedlandVincent MillischerGrant W MontgomeryJennifer L MoranDerek W MorrisThomas W MühleisenNiamh O'BrienClaire O'DonovanLoes M Olde LoohuisLilijana OrucSergi PapiolAntonio F PardiñasAmy PerryAndrea PfennigEvgenia PorichiJames B PotashDigby QuestedTowfique RajMark H RapaportJ Raymond DePauloEline J RegeerJohn P RiceFabio RivasMargarita RiveraJulian RothPanos RoussosDouglas M RuderferCristina Sánchez-MoraEva C SchulteFanny SennerSally SharpPaul D ShillingEngilbert SigurdssonLea SirignanoClaire SlaneyOlav B SmelandDaniel J SmithJanet L SobellChristine Søholm HansenMaria Soler ArtigasAnne T SpijkerDan J SteinJohn S StraussBeata ŚwiątkowskaChikashi TeraoThorgeir E ThorgeirssonClaudio TomaPaul TooneyEvangelia-Eirini TsermpiniMarquis P VawterHelmut VedderJames T R WaltersStephanie H WittSimon XiWei XuJessica Mei Kay YangAllan H YoungHannah YoungPeter P ZandiHang ZhouLea Zillichnull nullRolf AdolfssonIngrid AgartzMartin AldaLars AlfredssonGulja BabadjanovaLena BacklundBernhard T BauneFrank BellivierSusanne BengesserWade H BerrettiniDouglas H R BlackwoodMichael BoehnkeAnders D BørglumGerome BreenVaughan J CarrStanley CattsAiden CorvinNicholas CraddockUdo DannlowskiDimitris DikeosTõnu EskoBruno EtainPanagiotis FerentinosMark FryeJanice M FullertonMicha GawlikElliot S GershonFernando S GoesMelissa J GreenMaria Grigoroiu-SerbanescuJoanna HauserFrans HenskensJan HillertKyung Sue HongDavid M HougaardChristina M HultmanKristian HveemNakao IwataAssen V JablenskyIan JonesLisa A JonesRené S KahnJohn R KelsoeGeorge KirovMikael LandénMarion LeboyerCathryn M LewisQingqin S LiJolanta LissowskaChristine LochnerCarmel LoughlandNicholas G MartinCarol A MathewsFermin MayoralSusan L McElroyAndrew M McIntoshFrancis J McMahonIngrid MellePatricia MichieLili MilaniPhilip B MitchellGunnar MorkenOle MorsPreben Bo MortensenBryan MowryBertram Müller-MyhsokRichard M MyersBenjamin M NealeCaroline M NievergeltMerete NordentoftMarkus M NöthenMichael C O'DonovanKetil J OedegaardTomas OlssonMichael J OwenSara A PacigaChris PantelisCarlos PatoMichele T PatoGeorge P PatrinosRoy H PerlisDanielle PosthumaJosep Antoni Ramos-QuirogaAndreas ReifEva Z ReininghausMarta RibasésMarcella RietschelStephan RipkeGuy A RouleauTakeo SaitoUlrich SchallMartin SchallingPeter R SchofieldThomas G SchulzeLaura J ScottRodney J ScottAlessandro SerrettiCynthia Shannon WeickertJordan W SmollerHreinn StefanssonKari StefanssonEystein StordalFabian StreitPatrick F SullivanGustavo TureckiArne E VaalerEduard VietaJohn B VincentIrwin D WaldmanThomas W WeickertThomas WergeNaomi R WrayJohn-Anker ZwartJoanna M BiernackaJohn I NurnbergerSven CichonHoward J EdenbergEli A StahlAndrew McQuillinArianna Di FlorioRoel A OphoffOle Andreas Andreassen

Published in: Nature genetics (2021)

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.