Genome-wide association study identifies 30 Loci ...
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Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder 1 2 Eli A Stahl1,2,3†&, Gerome Breen4,5†, Andreas J Forstner6,7,8,9,10†, Andrew McQuillin11†, Stephan Ripke12,13,14†, Vassily 3 Trubetskoy13, Manuel Mattheisen15,16,17,18,19, Yunpeng Wang20,21, Jonathan R I Coleman4,5, Héléna A Gaspar4,5, Christiaan A 4 de Leeuw22, Stacy Steinberg23, Jennifer M Whitehead Pavlides24, Maciej Trzaskowski25, Tune H Pers3,26, Peter A Holmans27, Liam 5 Abbott12, Esben Agerbo19,28,29, Huda Akil30, Diego Albani31, Ney Alliey-Rodriguez32, Thomas D Als15,16,19, Adebayo Anjorin33, 6 Verneri Antilla14, Swapnil Awasthi13, Judith A Badner34, Marie Bækvad-Hansen19,35, Jack D Barchas36, Nicholas Bass11, Michael 7 Bauer37, Richard Belliveau12, Sarah E Bergen38, Carsten Bøcker Pedersen19,28,29, Erlend Bøen39, Marco Boks40, James 8 Boocock41, Monika Budde42, William Bunney43, Margit Burmeister44, Jonas Bybjerg-Grauholm19,35, William Byerley45, Miquel 9 Casas46,47,48,49, Felecia Cerrato12, Pablo Cervantes50, Kimberly Chambert12, Alexander W Charney2, Danfeng Chen12, Claire 10 Churchhouse12,14, Toni-Kim Clarke51, William Coryell52, David W Craig53, Cristiana Cruceanu50,54, David Curtis55,56, Piotr M 11 Czerski57, Anders M Dale58,59,60,61, Simone de Jong4,5, Franziska Degenhardt8,9, Jurgen Del-Favero62, J Raymond DePaulo63, 12 Srdjan Djurovic64,65, Amanda L Dobbyn1,2, Ashley Dumont12, Torbjørn Elvsåshagen66,67, Valentina Escott-Price27, Chun Chieh 13 Fan61, Sascha B Fischer6,10, Matthew Flickinger68, Tatiana M Foroud69, Liz Forty27, Josef Frank70, Christine Fraser27, Nelson B 14 Freimer71, Louise Frisén72,73,74, Katrin Gade42,75, Diane Gage12, Julie Garnham76, Claudia Giambartolomei41, Marianne Giørtz 15 Pedersen19,28,29, Jaqueline Goldstein12, Scott D Gordon77, Katherine Gordon-Smith78, Elaine K Green79, Melissa J Green80, 16 Tiffany A Greenwood60, Jakob Grove15,16,19,81, Weihua Guan82, José Guzman Parra83, Marian L Hamshere27, Martin 17 Hautzinger84, Urs Heilbronner42, Stefan Herms6,8,9,10, Maria Hipolito85, Per Hoffmann6,8,9,10, Dominic Holland58,86, Laura 18 Huckins1,2, Stéphane Jamain87,88, Jessica S Johnson1,2, Anders Juréus38, Radhika Kandaswamy4, Robert Karlsson38, James L 19 Kennedy89,90,91,92, Sarah Kittel-Schneider93, Sarah V Knott78, James A Knowles94,95, Manolis Kogevinas96, Anna C Koller8,9, 20 Ralph Kupka97,98,99, Catharina Lavebratt72, Jacob Lawrence100, William B Lawson85, Markus Leber101, Phil H Lee12,14,102, 21 Shawn E Levy103, Jun Z Li104, Chunyu Liu105, Susanne Lucae106, Anna Maaser8,9, Donald J MacIntyre107,108, Pamela B 22 Mahon63,109, Wolfgang Maier110, Lina Martinsson73, Steve McCarroll12,111, Peter McGuffin4, Melvin G McInnis112, James D 23 McKay113, Helena Medeiros95, Sarah E Medland77, Fan Meng30,112, Lili Milani114, Grant W Montgomery25, Derek W 24 Morris115,116, Thomas W Mühleisen6,117, Niamh Mullins4, Hoang Nguyen1,2, Caroline M Nievergelt60,118, Annelie Nordin 25 Adolfsson119, Evaristus A Nwulia85, Claire O'Donovan76, Loes M Olde Loohuis71, Anil P S Ori71, Lilijana Oruc120, Urban Ösby121, 26 Roy H Perlis122,123, Amy Perry78, Andrea Pfennig37, James B Potash63, Shaun M Purcell2,109, Eline J Regeer124, Andreas Reif93, 27 Céline S Reinbold6,10, John P Rice125, Fabio Rivas83, Margarita Rivera4,126, Panos Roussos1,2,127, Douglas M Ruderfer128, 28 Euijung Ryu129, Cristina Sánchez-Mora46,47,49, Alan F Schatzberg130, William A Scheftner131, Nicholas J Schork132, Cynthia 29 Shannon Weickert80,133, Tatyana Shehktman60, Paul D Shilling60, Engilbert Sigurdsson134, Claire Slaney76, Olav B 30 Smeland58,135,136, Janet L Sobell137, Christine Søholm Hansen19,35, Anne T Spijker138, David St Clair139, Michael Steffens140, 31 John S Strauss91,141, Fabian Streit70, Jana Strohmaier70, Szabolcs Szelinger142, Robert C Thompson112, Thorgeir E 32 Thorgeirsson23, Jens Treutlein70, Helmut Vedder143, Weiqing Wang1,2, Stanley J Watson112, Thomas W Weickert80,133, 33 Stephanie H Witt70, Simon Xi144, Wei Xu145,146, Allan H Young147, Peter Zandi148, Peng Zhang149, Sebastian Zollner112, Rolf 34 Adolfsson119, Ingrid Agartz17,39,150, Martin Alda76,151, Lena Backlund73, Bernhard T Baune152, Frank Bellivier153,154,155,156, 35 Wade H Berrettini157, Joanna M Biernacka129, Douglas H R Blackwood51, Michael Boehnke68, Anders D Børglum15,16,19, Aiden 36 Corvin116, Nicholas Craddock27, Mark J Daly12,14, Udo Dannlowski158, Tõnu Esko3,111,114,159, Bruno Etain153,155,156,160, 37 Mark Frye161, Janice M Fullerton133,162, Elliot S Gershon32,163, Michael Gill116, Fernando Goes63, Maria Grigoroiu- 38 Serbanescu164, Joanna Hauser57, David M Hougaard19,35, Christina M Hultman38, Ian Jones27, Lisa A Jones78, René S Kahn2,40, 39 George Kirov27, Mikael Landén38,165, Marion Leboyer88,153,166, Cathryn M Lewis4,5,167, Qingqin S Li168, Jolanta Lissowska169, 40 Nicholas G Martin77,170, Fermin Mayoral83, Susan L McElroy171, Andrew M McIntosh51,172, Francis J McMahon173, Ingrid 41 Melle174,175, Andres Metspalu114,176, Philip B Mitchell80, Gunnar Morken177,178, Ole Mors19,179, Preben Bo 42 Mortensen15,19,28,29, Bertram Müller-Myhsok54,180,181, Richard M Myers103, Benjamin M Neale3,12,14, Vishwajit 43 Nimgaonkar182, Merete Nordentoft19,183, Markus M Nöthen8,9, Michael C O'Donovan27, Ketil J Oedegaard184,185, Michael J 44 Owen27, Sara A Paciga186, Carlos Pato95,187, Michele T Pato95, Danielle Posthuma22,188, Josep Antoni Ramos- 45 Quiroga46,47,48,49, Marta Ribasés46,47,49, Marcella Rietschel70, Guy A Rouleau189,190, Martin Schalling72, Peter R 46 Schofield133,162, Thomas G Schulze42,63,70,75,173, Alessandro Serretti191, Jordan W Smoller12,192,193, Hreinn Stefansson23, 47 Kari Stefansson23,194, Eystein Stordal195,196, Patrick F Sullivan38,197,198, Gustavo Turecki199, Arne E Vaaler200, Eduard 48 Vieta201, John B Vincent141, Thomas Werge19,202,203, John I Nurnberger204, Naomi R Wray24,25, Arianna Di Florio27,198, 49 Howard J Edenberg205, Sven Cichon6,8,10,117, Roel A Ophoff40,41,71, Laura J Scott68, Ole A Andreassen135,136, John 50 Kelsoe60*&, Pamela Sklar1,2*^ 51 52 † Equal contribution * Co-last authors 53 & Correspondence to: [email protected] or [email protected] 54 ^ deceased. This paper is dedicated to the memory of Psychiatric Genomics Consortium founding member and Bipolar disorder 55 working group co-chair Pamela Sklar 56 57 58 59 . CC-BY 4.0 International license certified by peer review) is the author/funder. It is made available under a The copyright holder for this preprint (which was not this version posted January 24, 2018. . https://doi.org/10.1101/173062 doi: bioRxiv preprint
Transcript of Genome-wide association study identifies 30 Loci ...
Genome-wideassociationstudyidentifies30LociAssociatedwithBipolarDisorder12EliAStahl1,2,3†&,GeromeBreen4,5†,AndreasJForstner6,7,8,9,10†,AndrewMcQuillin11†,StephanRipke12,13,14†,Vassily3Trubetskoy13,ManuelMattheisen15,16,17,18,19,YunpengWang20,21,JonathanRIColeman4,5,HélénaAGaspar4,5,ChristiaanA4deLeeuw22,StacySteinberg23,JenniferMWhiteheadPavlides24,MaciejTrzaskowski25,TuneHPers3,26,PeterAHolmans27,Liam5Abbott12,EsbenAgerbo19,28,29,HudaAkil30,DiegoAlbani31,NeyAlliey-Rodriguez32,ThomasDAls15,16,19,AdebayoAnjorin33,6VerneriAntilla14,SwapnilAwasthi13,JudithABadner34,MarieBækvad-Hansen19,35,JackDBarchas36,NicholasBass11,Michael7Bauer37,RichardBelliveau12,SarahEBergen38,CarstenBøckerPedersen19,28,29,ErlendBøen39,MarcoBoks40,James8Boocock41,MonikaBudde42,WilliamBunney43,MargitBurmeister44,JonasBybjerg-Grauholm19,35,WilliamByerley45,Miquel9Casas46,47,48,49,FeleciaCerrato12,PabloCervantes50,KimberlyChambert12,AlexanderWCharney2,DanfengChen12,Claire10Churchhouse12,14,Toni-KimClarke51,WilliamCoryell52,DavidWCraig53,CristianaCruceanu50,54,DavidCurtis55,56,PiotrM11Czerski57,AndersMDale58,59,60,61,SimonedeJong4,5,FranziskaDegenhardt8,9,JurgenDel-Favero62,JRaymondDePaulo63,12SrdjanDjurovic64,65,AmandaLDobbyn1,2,AshleyDumont12,TorbjørnElvsåshagen66,67,ValentinaEscott-Price27,ChunChieh13Fan61,SaschaBFischer6,10,MatthewFlickinger68,TatianaMForoud69,LizForty27,JosefFrank70,ChristineFraser27,NelsonB14Freimer71,LouiseFrisén72,73,74,KatrinGade42,75,DianeGage12,JulieGarnham76,ClaudiaGiambartolomei41,MarianneGiørtz15Pedersen19,28,29,JaquelineGoldstein12,ScottDGordon77,KatherineGordon-Smith78,ElaineKGreen79,MelissaJGreen80,16TiffanyAGreenwood60,JakobGrove15,16,19,81,WeihuaGuan82,JoséGuzmanParra83,MarianLHamshere27,Martin17Hautzinger84,UrsHeilbronner42,StefanHerms6,8,9,10,MariaHipolito85,PerHoffmann6,8,9,10,DominicHolland58,86,Laura18Huckins1,2,StéphaneJamain87,88,JessicaSJohnson1,2,AndersJuréus38,RadhikaKandaswamy4,RobertKarlsson38,JamesL19Kennedy89,90,91,92,SarahKittel-Schneider93,SarahVKnott78,JamesAKnowles94,95,ManolisKogevinas96,AnnaCKoller8,9,20RalphKupka97,98,99,CatharinaLavebratt72,JacobLawrence100,WilliamBLawson85,MarkusLeber101,PhilHLee12,14,102,21ShawnELevy103,JunZLi104,ChunyuLiu105,SusanneLucae106,AnnaMaaser8,9,DonaldJMacIntyre107,108,PamelaB22Mahon63,109,WolfgangMaier110,LinaMartinsson73,SteveMcCarroll12,111,PeterMcGuffin4,MelvinGMcInnis112,JamesD23McKay113,HelenaMedeiros95,SarahEMedland77,FanMeng30,112,LiliMilani114,GrantWMontgomery25,DerekW24Morris115,116,ThomasWMühleisen6,117,NiamhMullins4,HoangNguyen1,2,CarolineMNievergelt60,118,AnnelieNordin25Adolfsson119,EvaristusANwulia85,ClaireO'Donovan76,LoesMOldeLoohuis71,AnilPSOri71,LilijanaOruc120,UrbanÖsby121,26RoyHPerlis122,123,AmyPerry78,AndreaPfennig37,JamesBPotash63,ShaunMPurcell2,109,ElineJRegeer124,AndreasReif93,27CélineSReinbold6,10,JohnPRice125,FabioRivas83,MargaritaRivera4,126,PanosRoussos1,2,127,DouglasMRuderfer128,28EuijungRyu129,CristinaSánchez-Mora46,47,49,AlanFSchatzberg130,WilliamAScheftner131,NicholasJSchork132,Cynthia29ShannonWeickert80,133,TatyanaShehktman60,PaulDShilling60,EngilbertSigurdsson134,ClaireSlaney76,OlavB30Smeland58,135,136,JanetLSobell137,ChristineSøholmHansen19,35,AnneTSpijker138,DavidStClair139,MichaelSteffens140,31JohnSStrauss91,141,FabianStreit70,JanaStrohmaier70,SzabolcsSzelinger142,RobertCThompson112,ThorgeirE32Thorgeirsson23,JensTreutlein70,HelmutVedder143,WeiqingWang1,2,StanleyJWatson112,ThomasWWeickert80,133,33StephanieHWitt70,SimonXi144,WeiXu145,146,AllanHYoung147,PeterZandi148,PengZhang149,SebastianZollner112,Rolf34Adolfsson119,IngridAgartz17,39,150,MartinAlda76,151,LenaBacklund73,BernhardTBaune152,FrankBellivier153,154,155,156,35WadeHBerrettini157,JoannaMBiernacka129,DouglasHRBlackwood51,MichaelBoehnke68,AndersDBørglum15,16,19,Aiden36Corvin116,NicholasCraddock27,MarkJDaly12,14,UdoDannlowski158,TõnuEsko3,111,114,159,BrunoEtain153,155,156,160,37MarkFrye161,JaniceMFullerton133,162,ElliotSGershon32,163,MichaelGill116,FernandoGoes63,MariaGrigoroiu-38Serbanescu164,JoannaHauser57,DavidMHougaard19,35,ChristinaMHultman38,IanJones27,LisaAJones78,RenéSKahn2,40,39GeorgeKirov27,MikaelLandén38,165,MarionLeboyer88,153,166,CathrynMLewis4,5,167,QingqinSLi168,JolantaLissowska169,40NicholasGMartin77,170,FerminMayoral83,SusanLMcElroy171,AndrewMMcIntosh51,172,FrancisJMcMahon173,Ingrid41Melle174,175,AndresMetspalu114,176,PhilipBMitchell80,GunnarMorken177,178,OleMors19,179,PrebenBo42Mortensen15,19,28,29,BertramMüller-Myhsok54,180,181,RichardMMyers103,BenjaminMNeale3,12,14,Vishwajit43Nimgaonkar182,MereteNordentoft19,183,MarkusMNöthen8,9,MichaelCO'Donovan27,KetilJOedegaard184,185,MichaelJ44Owen27,SaraAPaciga186,CarlosPato95,187,MicheleTPato95,DaniellePosthuma22,188,JosepAntoniRamos-45Quiroga46,47,48,49,MartaRibasés46,47,49,MarcellaRietschel70,GuyARouleau189,190,MartinSchalling72,PeterR46Schofield133,162,ThomasGSchulze42,63,70,75,173,AlessandroSerretti191,JordanWSmoller12,192,193,HreinnStefansson23,47KariStefansson23,194,EysteinStordal195,196,PatrickFSullivan38,197,198,GustavoTurecki199,ArneEVaaler200,Eduard48Vieta201,JohnBVincent141,ThomasWerge19,202,203,JohnINurnberger204,NaomiRWray24,25,AriannaDiFlorio27,198,49HowardJEdenberg205,SvenCichon6,8,10,117,RoelAOphoff40,41,71,LauraJScott68,OleAAndreassen135,136,John50Kelsoe60*&,PamelaSklar1,2*^5152†Equalcontribution*Co-lastauthors53&Correspondenceto:[email protected]@mssm.edu54^deceased.ThispaperisdedicatedtothememoryofPsychiatricGenomicsConsortiumfoundingmemberandBipolardisorder55workinggroupco-chairPamelaSklar565758 59
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
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ABSTRACT:2
Bipolardisorderisahighlyheritablepsychiatricdisorderthatfeaturesepisodesofmaniaand3
depression.Weperformedthelargestgenome-wideassociationstudytodate,including20,3524
casesand31,358controlsofEuropeandescent,withfollow-upanalysisof822sentinelvariants5
atlociwithP<1x10-4inanindependentsampleof9,412casesand137,760controls.Inthe6
combinedanalysis,30locireachedgenome-widesignificantevidenceforassociation,ofwhich7
20werenovel.Thesesignificantlocicontaingenesencodingionchannelsandneurotransmitter8
transporters(CACNA1C,GRIN2A,SCN2A,SLC4A1),synapticcomponents(RIMS1,ANK3),immune9
andenergymetabolismcomponents.BipolardisordertypeI(depressiveandmanicepisodes;10
~73%ofourcases)isstronglygeneticallycorrelatedwithschizophreniawhereasbipolar11
disordertypeII(depressiveandhypomanicepisodes;~17%ofourcases)ismorestrongly12
correlatedwithmajordepressivedisorder.Thesefindingsaddresskeyclinicalquestionsand13
providepotentialnewbiologicalmechanismsforbipolardisorder.14
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.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
INTRODUCTION1
Bipolardisorder(BD) isasevereneuropsychiatricdisordercharacterizedbyrecurrentepisodes2
ofmania and depression which affect thought, perception, emotion, and social behaviour. A3
lifetimeprevalenceof1-2%,elevatedmorbidityandmortality,onsetinyoungadulthood,anda4
frequently chronic coursemakeBDamajorpublichealthproblemanda leading causeof the5
globalburdenofdisease1.Clinical,twinandmoleculargeneticdataallstronglysuggestthatBD6
is a multifactorial disorder 2. Based on twin studies, the overall heritability of BD has been7
estimatedtobemorethan70%3,4,suggestingasubstantialinvolvementofgeneticfactorsinthe8
developmentofthedisorder,althoughnon-geneticfactorsalsoinfluencerisk.9
BDcanbedividedintotwomainclinicalsubtypes5,6:bipolarIdisorder(BD1)andbipolar10
IIdisorder(BD2).InBD1,manicepisodestypicallyalternatewithdepressiveepisodesduringthe11
courseofillness.DiagnosisofBD2isbasedonthelifetimeoccurrenceofatleastonedepressive12
and one hypomanic (but nomanic) episode. Althoughmodern diagnostic systems retain the13
Kraepelinian dichotomy 7 between BD and schizophrenia, the distinction between the two14
disorders is not always clear-cut, and patientswho display clinical features of both disorders15
may receiveadiagnosisof schizoaffectivedisorder (SAB). Likewise, in genetic studies the two16
diagnosesareusuallytreatedseparately,althoughrecentepidemiologicalandmoleculargenetic17
studies provide strong evidence for some overlap between the genetic contributions to their18
etiology2,8.19
Recent genome-wide association studies (GWAS) in BD have identified a number of20
significantassociationsbetweendiseasestatusandcommongeneticvariants9–23.Thefirstlarge21
collaborative BD GWAS by the multinational Psychiatric Genomics Consortium (PGC) Bipolar22
DisorderWorking Group comprised 7,481 BD patients and 9,250 controls and identified four23
genome-widesignificantloci9.Threesubsequentmeta-analysesthatincludedthePGCBDdata24
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
10,12,18identifiedanadditional5loci.1
Estimates of the proportion of variance in liability attributable to common variants2
genome-wide(SNP-heritability) indicatethat~30%oftheheritabilityforBDisduetocommon3
geneticvariants8.Todate,onlyasmallfractionofthisheritabilityisexplainedbyassociatedloci,4
but results from other human complex traits suggest that many more will be identified by5
increasing thesamplesizeofGWAS24. Here,wereport thesecondGWASof thePGCBipolar6
DisorderWorkingGroup,comprising20,352casesand31,358controlsofEuropeandescentina7
single, systematic analysis,with follow up of top findings in an independent sample of 9,4128
cases and 137,760 controls. Some of our findings reinforce specific hypotheses regarding BD9
neurobiology;however,themajorityofthefindingssuggestnewbiologicalinsights.10
11
RESULTS12
GWASofbipolardisorder(BD)13
WeperformedaGWASmeta-analysisof32cohortsfrom14countriesinEurope,NorthAmerica14
andAustralia(SupplementaryTable1A),totaling20,352casesand31,358controlsofEuropean15
descent(effectivesamplesize46,582).ThisisthelargestGWASofBDtodateandincludes6,32816
caseand7,963controlsamplesnotpreviouslyreported,a2.7-foldincreaseinthenumberof17
casescomparedtoourpreviousGWAS9.Weimputedvariantdosagesusingthe1,000Genomes18
referencepanel(seeMethods),retainingassociationresultsfor9,372,253autosomalvariants19
withimputationqualityscoreINFO>0.3andminorallelefrequency≥1%inbothcasesand20
controls.Weperformedlogisticregressionofcasestatusonimputedvariantdosageusing21
geneticancestrycovariates.Theresultinggenomicinflationfactor(λGC)was1.23andscaledto22
1,000casesand1,000controls(λ1000)was1.01(SupplementaryFigure1).TheLD-score23
regressioninterceptdidnotsignificantlydifferfromone,indicatingthattheobservedgenomic24
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
inflationisindicativeofpolygenicityratherthanstratificationorcrypticpopulationstructure25.1
TheLD-scoreregressionSNP-heritabilityestimatesforBDwere0.17-0.23(ontheliabilityscale,2
assumingpopulationlifetimeriskof0.5-2%).SeeSupplementaryTable1A,OnlineMethods3
andSupplementaryNoteforsampleandmethoddetails.4
Wefindamarkedincreaseinphenotypicvarianceexplainedbygenomewidepolygenic5
riskscores(PRS)comparedtopreviouspublications(samplesizeweightedmeanobserved6
Nagelkerke’sR2=0.08acrossdatasets,liabilityscaleR2=0.04,forP-threshold�0.01;7
SupplementaryFigure2andSupplementaryTable2).Amongthedifferentdatasets,we8
observednoassociationbetweenthePRSand:(i)thegenderdistributionoftheBDcases9
(p=0.51);(ii)theproportionofcaseswithpsychosis(p=0.61);(iii)theproportionwithafamily10
historyofBD(p=0.82);or(iv)themedianageofonsetforBD(p=0.64).Inourprimarygenome-11
wideanalysis,weidentified19lociexceedinggenome-widesignificance(P<5x10-8).12
13
Follow-upofsuggestivelociinadditionalsamples14
Wemeta-analyzedleadvariantsthatweresignificantatP<1x10-4inourdiscoverymeta-analysis,15
(atotalof794autosomaland28Xchromosomevariants)withfollow-upsamplestotaling9,41216
casesand137,760controlsofEuropeanancestry(SupplementaryNoteandSupplementary17
Table1B).Thirtyautosomallociachievedcombinedsamplegenome-widesignificance(P<5x10-18
8)(Figure1,Table1,SupplementaryFigure3,SupplementaryTable3).Theseinclude19loci19
thatweresignificantonlyinthecombinedanalysis,ofwhichthreewerereportedtohave20
genome-widesignificantSNPsinpreviousstudies(ADCY218,POU3F218,ANK312,18),and11that21
weresignificantinourGWAS.Eightvariantsweregenome-widesignificantintheGWASbutnot22
inthecombinedanalysis.Usingeffectsizescorrectedforwinner’scurse26,27foreachofthe1923
variantswithGWASP<5x10-8,wefoundthat11variantsachievinggenome-widesignificancein24
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
ourcombinedanalysisiswithintheexpectedrange(PoissonbinomialtestP=0.29,1
SupplementaryNoteandSupplementaryFigure4).2
Leadvariantsforthe30lociachievinggenome-widesignificanceinthecombined3
analysisareshowninTable1A.WeshowresultsinTable1Bfor8additionallociwithP<5x10-84
inourdiscoveryGWASbutnotinthecombinedanalysis.Resultsforallvariantstestedinthe5
follow-upstudyarepresentedinSupplementaryTable3.Werefertolocibythegenename6
attributedinpreviousBDGWASpublications,orbythenameoftheclosestgenefornovelloci,7
withoutimplicationthatthenamedgeneiscausal.Ofthe30genome-widesignificantlocifrom8
ourcombinedanalysis,20arenovelBDriskloci.InSupplementaryTable4,wepresentdetailed9
descriptionsoftheassociatedlociandgenes,withbioinformaticandliteratureevidencefor10
theirpotentialrolesinBD.11
12
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2Figure1.Manhattanplotforourprimarygenomewideassociationanalysisof20,352casesand31,358controls.GWAS-log10P-valuesareplottedforallSNPsacrosschromosomes1-22(diamonds,greenforlociwithleadSNPGWASP<10-6).CombinedGWAS+followup-log10P-valuesforleadSNPsreachinggenome-widesignificanceineitherGWASorcombinedanalysis(triangles,invertedifGWAS+followup-log10P>GWAS-log10P).Labelscorrespondtogenesymbolspreviouslyreportedforpublishedloci(black)andthenearestgenesfornovelloci(blue),attopifGWAS+followupP<5x10-8.
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Wenextaskedifthevariantstestedinthefollow-upsampleswere,inaggregate,2
consistentwiththepresenceofadditionalsubgenome-widesignificantBDassociationsignals.3
Afterexcluding47variantsthatweregenome-widesignificantinourGWAS,ourcombined4
analysisorpreviousBDGWAS,775variantsremainedinourfollow-upexperiment.551variants5
hadthesamedirectionofeffectinthediscoveryGWASandfollow-upsamples(71%compared6
toanullexpectationof50%,signtestP<2.2x10-16),and110variantshadthesamedirectionof7
effectandwerenominallysignificant(p<0.05)inthefollow-upsamples(14%comparedtoan8
expectedvalueof2.5%,binomialtestP<2.2x10-16).ThisconsistencybetweenourGWASand9
follow-upsamplessuggeststhatmanytrueBDassociationsexistamongthesevariants.10
Toidentifyadditionalindependentsignals,weconductedconditionalanalysesacross11
eachofthe30significantBDloci(SupplementaryTable5).Weusedtheeffectivenumberof12
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independentvariantsbasedonLDstructurewithinloci28tocalculateamultipletest-corrected1
significancethreshold(P=1.01x10-5,seeSupplementaryNote).Onelocusshowedevidencefor2
anindependentassociationsignal(rs114534140inlocus#8,FSTL5;Pconditional=2x10-6).Atone3
locus(#30,STK4onchr20),wefoundtwoSNPswithgenome-widesignificanceinlowLD(r2<4
0.1);however,conditionalanalysisshowedthattheirassociationswerenotindependent.Thus5
onlytheFSTL5locusdemonstratedclearevidenceofmorethanoneindependentassociation.6
7
Sharedlociandgeneticcorrelationswithschizophrenia,depressionandotherGWAStraits8
WenextexaminedthegeneticrelationshipsofBDtootherpsychiatricdisordersandtraits.Of9
the30genome-widesignificantBDloci,8alsoharborschizophrenia(SCZ)associations29–31.10
BasedonconditionalanalysestheBDandSCZassociationsappeartobeindependentat3ofthe11
8sharedloci(NCAN,TRANK1andchr7q22.3:105Mbloci)(SupplementaryTable6).Nogenome-12
widesignificantBDlocusoverlappedwiththoseidentifiedformajordepression(DEPR),13
including44risklociidentifiedinthemostrecentPGCstudybasedon130,664depressioncases14
and330,470controls32,andthosereportedinalargestudyofdepressivesymptomsor15
subjectivewell-being33.Aspreviouslyreported34,wefoundsubstantialandhighlysignificant16
geneticcorrelationsbetweenBDandSCZ(LD-scoreregressionestimatedgeneticcorrelationrg=17
0.70,se=0.020)andbetweenBDandDEPR(rg=0.35,se=0.026)TheBDandDEPRgenetic18
correlationwassimilartothatobservedforSCZandDEPR(rg=0.34,se=0.025)(Supplementary19
Table7A).20
WefoundsignificantgeneticcorrelationsbetweenBDandotherpsychiatric-relevant21
traits(SupplementaryTable7B),includingwithautismspectrumdisorder8(rg=0.18,P=2x10-4),22
anorexianervosa35(rg=0.23,P=9x10-8),andsubjectivewell-being33(rg=-0.22,P=4x10-7).There23
wassuggestivepositiveoverlapwithanxietydisorders(rg=0.21,P=0.04)36andneuroticism24
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(rg=0.12,P=0.002)37.Significantrgswereseenwithmeasuresofeducation:collegeattendance1
38(rg=0.21,P=1=x10-7)andeducationyears39(rg=0.20,P=6x10-14),butnotwithchildhoodIQ402
(rg=0.05,P=0.5)orintelligence41(rg=-0.05,P=0.08).AmongalargenumberofBDrisklocusSNPs3
associatedwithadditionaltraitsfromGWAScatalog,wefoundahandfuloflociwithnon-4
independentassociations(inoneoverlappinglocuseachwitheducationalattainment,biliary5
atresia,bonemineraldensity,lipid-relatedbiomarkers)(SupplementaryTable6).Biliaryatresia6
andlipid-relatedbiomarkers,however,didnotshowsignificantgeneticcorrelationwithBD7
(SupplementaryTable7B).8
9
BDsubtypeGWAS10
WeperformedsecondaryGWASfocusingonthreeclinicallyrecognizedsubtypesofbipolar11
disorder:BD1(n=14,879cases),BD2(n=3,421cases),andSAB(n=977cases)(Supplementary12
Note,SupplementaryTables1A&8,SupplementaryFigure5).Weobservedvariantsin14loci13
withgenome-widesignificanceforBD1,10ofwhichwereingenome-widesignificantlociinthe14
combinedBDGWASanalysis.Notsurprisinglygiventhesampleoverlap,3ofthe4remainingloci15
genome-widesignificantforBD1haveP<10-6ineitherourGWASorcombinedanalysis.The16
remaininglocus(MAD1L1,chr7:1.9Mb,GWASP=2.4x10-6)wasrecentlypublishedintwoBD17
GWASthatincludedAsiansamples42,43.Wedidnotobservegenome-widesignificantresultsfor18
thesmallerBD2andSABanalyses.BD1,BD2andSABallhavesignificantcommonvariant19
heritabilities(BD1h2snp=0.25,se=0.014,P=3.2x10-77;BD2h2snp=0.11,se=0.028,P=5.8x10-5;20
SABh2snp=0.25,se=0.10,P=0.0071).GeneticcorrelationsamongBDsubtypesshowthatthese21
representcloselyrelated,yetpartiallydistinct,phenotypes(SupplementaryTable9).22
PolygenicriskscoresandgeneticcorrelationsprovidesupportforacontinuumofSCZ-23
BD1-BD2-DEPRgeneticeffects,withsignificantlygreatergeneticSCZpolygenicriskscores(PRS)24
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inBD1casesthaninBD2cases(minP=5.6x10-17,Pthreshold=0.1),andgreaterDEPRPRSinBD21
casesthaninBD1cases(minP=8.5x10-10,Pthreshold=0.01)(Figure2,SupplementaryTable2
10).GeneticcorrelationsfromLD-scoreregressionsupporttheseresults;geneticcorrelations3
weregreaterforSCZwithBD1(rg=0.71,se=0.025)thanwithBD2(rg=0.51,se=0.072),with4
Pdiff=0.0056,andweregreaterforDEPRwithBD2(rg=0.69,se=0.093)thanwithBD1(rg=5
0.30,se=0.028),withPdiff=2.9x10-5(SupplementaryTable9).6
7
8
Figure2.AssociationofBD1andBD2subtypeswithschizophrenia(SCZ)andmajordepression(DEPR)polygenicriskscores(PRS).ShownaremeanPRSvalues(1s.e.errorbars),adjustedforstudyandancestrycovariatesandscaledtothePRSmeanandsdincontrolsubjects,inBD1(red)andBD2(blue)cases,forincreasingsourceGWASP-valuethresholds(increasinggrey)asindicated.P-values(italics)testBD1vsBD2meanPRS,inlogisticregressionofcasesubtypeonPRSwithcovariates.ResultsaredetailedinSupplementaryTable10.
9
10
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SystemsbiologyandinsilicofunctionalanalysesofBDGWASresults1
Toidentifygeneswithfunctionalvariationingeneexpressionthatmightexplainthe2
associations,weusedsummaryMendelianrandomization(SMR)44tointegrateourBDdiscovery3
GWASwitheQTLdatafrombraindorsolateralprefrontalcortex45aswellasalarge-sample4
wholebloodeQTLdataset46(SupplementalTable11).SMRidentifiedsixtranscriptome-wide5
significantgeneswithoutsignsofheterogeneitybetweenGWASandeQTLassociationsignals.6
Amongthese,fourgeneswerepresentinfourdifferentlocifromourcombinedBDGWASand7
follow-upsamplemeta-analysis:LMAN2L(blood),FADS1(brain),NMB(blood)andC17ORF658
(blood).9
WetestedforfunctionalgenomicenrichmentinourBDGWASusingpartitionedLD-10
scoreregression47(SupplementaryNote,SupplementaryTable12).Annotationstested11
includedopenchromatinDHSpeaksinarangeoftissues48,genicannotations,conservation,12
andanumberoffunctionalgenomicannotationsacrosstissues.SNP-basedBDheritabilitywas13
mostsubstantiallyenrichedinopenchromatinannotationsincentralnervoussystem14
(proportionSNPs=0.14,proportionh2snp=0.60,enrichment=3.8,P=4.2x10-17).Wealsoused15
DEPICT49totestforexpressionofBDassociatedgenesacrosstissues,andfoundsignificant16
enrichmentofcentralnervoussystem(P<=1.3x10-3,FDR<0.01)andneurosecretorysystem(P17
<=2.0x10-6,FDR<0.01)genes(SupplementaryTable13).18
Finally,weusedMAGMA50toconductagene-wiseBDGWASandtotestforenrichment19
ofpathwayscuratedfrommultiplesources(seeSupplementaryNote).Wenotethat20
significancelevelswereassignedtogenesbyphysicalproximityofSNPs,anddonotimplythat21
significantgenesarecausalforBD.Genicassociationresultsincluded154Bonferronisignificant22
genes(MAGMAP_JOINT<2.8x10-6),including82genesin20genome-widesignificantloci,and23
73genesin27additionallocithatdidnotreachgenome-widesignificanceineitherourGWASor24
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combinedanalysis(SupplementaryTable14).Ninerelatedpathwaysweresignificantlyenriched1
forgeneswithstrongerBDassociations(P<7.0x10-5,FDR<0.05),includingabnormalmotor2
coordination/balancepathways(frommice),regulationofinsulinsecretionand3
endocannabinoidsignalingpathways(SupplementaryTable15,SupplementaryFigure6).4
DISCUSSION5
Wecarriedoutthelargestbipolardisorder(BD)GWAStodateandidentified306
genome-widesignificantloci,including20novelBDriskloci.PreviousBDGWAShavereporteda7
totalof20locisignificantlyassociatedwithBD9–23 ;twelveofthesepreviouslyreportedlociwere8
notgenome-widesignificantinourGWASmetaanalysisbuthadPGWAS≤1.3x10-5.Ofthe19loci9
identifiedinourdiscoveryGWAS,only11weregenome-widesignificantinmeta-analysisofour10
GWASandfollow-upsamples.Althoughtheseresultsarenotunexpectedgivensmalleffectsizes11
andthewinner’scurse27,51(SupplementaryNoteandSupplementaryFigure4),genetic12
heterogeneityhasbeenshownbetweenBDGWAScohorts8.Weobservedvariablepolygenic13
effectsbetweenBDsubtypesandbetweencohortsinourstudy(Figure2,SupplementaryFigure14
2,SupplementaryTables2&10)andacknowledgeadiversityofclinicalcasephenotypiccriteria15
amongcohortsinourstudy(SupplementaryNote).Remarkably,ourstrongestassociation16
signal,observedattheTRANK1locus(rs9834970;Pcombined=5.7E-12,OR=0.93),exhibited17
significantheterogeneityamongdiscoveryGWAScohorts(Cochran’sQP=1.9x10-4,anddidnot18
replicateinthefollow-upsample(1-tailedPfollowup=0.3)(SupplementaryFigure3B&3C,fifth19
andfirstplotsrespectively).Thislocushasbeenobservedinrecent11,12,17,18butnotearlierBD20
GWAS9,13,20,surprisinglygivenitsrelativelylargeapparenteffectsize.Thus,complexpolygenic21
architectureaswellasphenotypicheterogeneityamongBDGWAScohortsmaycontributeto22
theinconsistencyofgenome-widesignificantfindingswithinandacrossBDGWASstudies.The23
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observedheterogeneityisamajorchallengeforGWASofpsychiatricdisordersandcallsfor1
carefulandsystematicclinicalassessmentofcasesandcontrolsinadditiontocontinuedefforts2
tocollectlargersamplesizes.3
Ofthe30BDassociatedloci,8alsoharborassociations29–31withschizophrenia(SCZ);4
however,conditionalanalysessuggestthattheBDandSCZassociationsat3ofthe8sharedloci5
(intheNCAN,TRANK1andchr7q22.3[105Mb]loci)maybeindependent(SupplementaryTable6
6).DifferentialBDandSCZassociationsmayrepresentopportunitiestounderstandthegenetic7
distinctionsbetweenthesecloselyrelatedandsometimesclinicallydifficulttodistinguish8
disorders.WedidnotfindBDlocithatoverlapwiththoseassociatedwithmajordepression32.9
TheconfirmedassociationwithinlocicontainingCACNA1Candothervoltage-gated10
calciumchannelssupportstherekindledinterestincalciumchannelantagonistsaspotential11
treatmentsforBDwithsimilarexaminationongoingforothergenesimplicatedbycurrent12
GWAS52.Theseprocessesareimportantinneuronalhyperexcitability53,anexcessofwhichhas13
beenreportediniPSCderivedneuronsfromBDpatients,andwhichhasbeenshowntobe14
affectedbytheclassicmoodstabilizingdruglithium54.Othergeneswithinnovelassociatedloci15
includethosecodingforneurotransmitterchannels(GRIN2A),ionchannelsandtransporters16
(SCN2A,SLC4A1)andsynapticcomponents(RIMS1,ANK3).Furtherstudywillconfirmwhether17
ornotthesearethecausalgenesintheseloci.18
Theestimatedvarianceexplainedbypolygenicriskscores(PRS)basedonourBDGWAS19
datais~8%(observedscale;4%ontheliabilityscale55),anincreasefrom2.8%fromour20
previousstudy9.UsingPRS,wefoundthatBD1caseshavesignificantlygreaterschizophrenia21
geneticriskthanBD2cases,whileBD2caseshavesignificantlygreatermajordepressiongenetic22
riskthanBD1cases,consistentwithaspectrumofrelatedpsychiatricdiagnoses7,56.Weobserve23
significantpositivegeneticcorrelationswitheducationalattainment,butnotwitheitheradultor24
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childhoodIQ,suggestingthattheroleofBDgeneticsinincreasededucationalattainmentmay1
beindependentofgeneralintelligence.Thisresultisinconsistentwithsuggestionsfrom2
epidemiologicalstudies57,butinagreementwitharecentclinicalstudy58.3
Insummary,findingsfromthelargestgenome-wideanalysisofBDrevealanextensive4
polygenicgeneticarchitectureofthedisease,implicatebraincalciumchannelsand5
neurotransmitterfunctioninBDetiology,andconfirmthatBDispartofaspectrumofhighly6
correlatedpsychiatricandmooddisorders.7
8
ONLINEMETHODS9
Methods10
GWASandfollow-upcohorts.OurdiscoveryGWASsamplewascomprisedof32cohortsfrom11
14countriesinEurope,NorthAmericaandAustralia(SupplementaryTable1A),totaling20,35212
casesand31,358controlsofEuropeandescent.Aselectedsetofvariants(seebelow)were13
testedin7follow-upcohortsofEuropeandescent(SupplementaryTable1B),totalling9,02514
casesand142,824controls(Neff=23,991).TheSupplementaryNotesummarizesthesourceand15
inclusion/exclusioncriteriaforcasesandcontrolsforeachcohort.AllcohortsintheinitialPGC16
BDpaperwereincluded9.Caseswererequiredtomeetinternationalconsensuscriteria(DSM-17
IV,ICD-9,orICD-10)foralifetimediagnosisofBDestablishedusingstructureddiagnostic18
instrumentsfromassessmentsbytrainedinterviewers,clinician-administeredchecklists,or19
medicalrecordreview.Inmostcohorts,controlswerescreenedfortheabsenceoflifetime20
psychiatricdisordersandrandomlyselectedfromthepopulation.21
GWAScohortanalysisWetested20principalcomponentsforassociationwithBDusinglogistic22
regression;sevenweresignificantlyassociatedwithphenotypeandusedinGWASassociation23
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analysis(PCs1-6,19).Ineachcohort,weperformedlogisticregressionassociationtestsforBD1
withimputedmarkerdosagesincluding7principalcomponentstocontrolforpopulation2
stratification.ForallGWAScohorts,X-chromosomeassociationanalyseswereconducted3
separatelybysex,andthenmeta-analyzedacrosssexes.WealsoconductedBD1,BD2,andSAB4
GWAS,retainingonlycohortswithatleast35subtypecasesandfilteringSNPsforMAF>0.02.5
Resultswerecombinedacrosscohortsusinganinversevariance-weightedfixedeffectsmeta-6
analysis59.WeusedPlink‘clumping’60,61toidentifyanLD-prunedsetofdiscoveryGWASmeta-7
analysisBD-associatedvariants(P<0.0001,anddistance>500kborLDr2<0.1,nvariants=822)8
foranalysisinthefollow-upcohorts.ConditionalanalyseswereconductedwithineachGWAS9
cohortandmeta-analyzedasabove.10
Follow-upcohortanalysis.Ineachfollow-upcohortweperformedBDassociationanalysisofthe11
822selectedGWASvariants(whenavailable)includinggeneticancestrycovariates,followingQC12
andanalysismethodsoftheindividualstudycontributors.Weperformedinversevariance-13
weightedfixed-effectsmeta-analysesoftheassociationresultsfromthefollow-upcohorts,and14
ofthediscoveryGWASandfollow-upanalyses.15
Polygenicriskscore(PRS)analyses.WetestedPRSforourprimaryGWASoneachGWAScohort16
asatargetset,usingaGWASwherethetargetcohortwasleftoutofthemeta-analysis17
(SupplementaryTable2).Totestgeneticoverlapswithotherpsychiatricdiseases,wecalculated18
PRSforDEPRandSCZinourGWAScohortBDcases62.Inpairwisecasesubtypeanalyses(Figure19
2,SupplementaryTable10),weregressedsubtypecasestatus(BD1n=8044,BD2n=3,365,SAB20
n=977)onthePRSadjustingforancestryprincipalcomponentsandacohortindicatorusing21
logisticregression,andvisualizedcovariate-adjustedPRSinBD1andBD2subtypes(Figure2).22
Linkagedisequilibrium(LD)scoreregression.LDscoreregression25,63wasusedtoconductSNP-23
heritabilityanalysesfromGWASsummarystatistics.LDscoreregressionbivariategenetic24
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correlationsattributabletogenome-widecommonvariantswereestimatedbetweenthefullBD1
GWAS,BDsubtypeGWASs,andothertraitsanddisorderswithLD-Hub63.WealsousedLDscore2
regressiontopartitionheritabilitybygenomicfeatures47.3
RelationofBDGWAfindingstotissueandcellulargeneexpression.WeusedpartitionedLD4
scoreregressiontoevaluatewhichsomatictissuesandbraintissueswereenrichedforBD5
heritability.64Weusedsummary-data-basedMendelianrandomization(SMR)44toidentifyloci6
withstrongevidenceofcausalityviageneexpression(SupplementaryTable9).Sincetheaimof7
SMRistoprioritizevariantsandgenesforsubsequentstudies,atestforheterogeneityexcludes8
regionsthatmayharbormultiplecausalloci(pHET<0.05).9
Gene-wiseandpathwayanalysis.GuidedbyrigorousmethodcomparisonsconductedbyPGC10
members50,65,p-valuesquantifyingthedegreeofassociationofgenesandgenesetswithBD11
weregeneratedusingMAGMA(v1.06)50.WeusedENSEMBLgenecoordinatesfor18,172genes12
givingaBonferronicorrectedP-valuethresholdof2.8x10-6.Jointmulti-SNPLD-adjustedgene-13
levelp-valueswerecalculatedusingSNPs35kbupstreamto10kbdownstream,adjustingforLD14
using1,000GenomesProject(Phase3v5a,MAF≥0.01,European-ancestrysubjects)66.Gene15
setswerecompiledfrommultiplesources.Competitivegenesettestswereconducted16
correctingforgenesize,variantdensity,andLDwithinandbetweengenes.Thepathwaymap17
(SupplementaryFigure6)wasconstructedusingthekernelgenerativetopographicmapping18
algorithm(k-GTM)asdescribedby67.SeeSupplementaryNoteforfurtherdetails.19
Genomebuild.AllgenomiccoordinatesaregiveninNCBIBuild37/UCSChg19.20
Availabilityofresults.ThePGC’spolicyistomakegenome-widesummaryresultspublic.21
Summarystatisticsforourmeta-analysisoftheGWAScohortsamplesareavailablethroughthe22
PGC(URLs).23
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URLs1
PsychiatricGenomicsConsortium,PGC,https://med.unc.edu/pgc2
PGC“ricopili”GWApipeline,https://github.com/Nealelab/ricopili3
1000GenomesProjectmulti-ancestryimputationpanel,4
https://mathgen.stats.ox.ac.uk/impute/data_download_1000G_phase1_integrated.html5
LD-Hub,http://ldsc.broadinstitute.org6
GTEx,http://www.gtexportal.org/home/datasets7
CommonMindConsortium,http://commonmind.org8
9
10
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Affiliations:1
1DepartmentofGeneticsandGenomicSciences,IcahnSchoolofMedicineatMountSinai,NewYork,NY,2US32DepartmentofPsychiatry,IcahnSchoolofMedicineatMountSinai,NewYork,NY,US43MedicalandPopulationGenetics,BroadInstitute,Cambridge,MA,US54MRCSocial,GeneticandDevelopmentalPsychiatryCentre,King'sCollegeLondon,London,GB65NIHRBRCforMentalHealth,King'sCollegeLondon,London,GB76DepartmentofBiomedicine,UniversityofBasel,Basel,CH87DepartmentofPsychiatry(UPK),UniversityofBasel,Basel,CH98InstituteofHumanGenetics,UniversityofBonn,Bonn,DE109Life&BrainCenter,DepartmentofGenomics,UniversityofBonn,Bonn,DE1110InstituteofMedicalGeneticsandPathology,UniversityHospitalBasel,Basel,CH1211DivisionofPsychiatry,UniversityCollegeLondon,London,GB1312StanleyCenterforPsychiatricResearch,BroadInstitute,Cambridge,MA,US1413DepartmentofPsychiatryandPsychotherapy,Charité-Universitätsmedizin,Berlin,DE1514AnalyticandTranslationalGeneticsUnit,MassachusettsGeneralHospital,Boston,MA,US1615iSEQ,CenterforIntegrativeSequencing,AarhusUniversity,Aarhus,DK1716DepartmentofBiomedicine-HumanGenetics,AarhusUniversity,Aarhus,DK1817DepartmentofClinicalNeuroscience,CentreforPsychiatryResearch,KarolinskaInstitutet,Stockholm,19SE2018DepartmentofPsychiatry,PsychosomaticsandPsychotherapy,CenterofMentalHealth,University21HospitalWürzburg,Würzburg,DE2219iPSYCH,TheLundbeckFoundationInitiativeforIntegrativePsychiatricResearch,DK2320InstituteofBiologicalPsychiatry,MentalHealthCentreSct.Hans,Copenhagen,DK2421InstituteofClinicalMedicine,UniversityofOslo,Oslo,NO2522DepartmentofComplexTraitGenetics,CenterforNeurogenomicsandCognitiveResearch,Amsterdam26Neuroscience,VrijeUniversiteitAmsterdam,Amsterdam,NL2723deCODEGenetics/Amgen,Reykjavik,IS2824QueenslandBrainInstitute,TheUniversityofQueensland,Brisbane,QLD,AU2925InstituteforMolecularBioscience,TheUniversityofQueensland,Brisbane,QLD,AU3026DivisionofEndocrinologyandCenterforBasicandTranslationalObesityResearch,BostonChildren’s31Hospital,Boston,MA,US3227MedicalResearchCouncilCentreforNeuropsychiatricGeneticsandGenomics,Divisionof33PsychologicalMedicineandClinicalNeurosciences,CardiffUniversity,Cardiff,GB3428NationalCentreforRegister-BasedResearch,AarhusUniversity,Aarhus,DK3529CentreforIntegratedRegister-basedResearch,AarhusUniversity,Aarhus,DK3630Molecular&BehavioralNeuroscienceInstitute,UniversityofMichigan,AnnArbor,MI,US3731NEUROSCIENCE,IstitutoDiRicercheFarmacologicheMarioNegri,Milano,IT3832DepartmentofPsychiatryandBehavioralNeuroscience,UniversityofChicago,Chicago,IL,US3933Psychiatry,BerkshireHealthcareNHSFoundationTrust,Bracknell,GB4034Psychiatry,RushUniversityMedicalCenter,Chicago,IL,US4135CenterforNeonatalScreening,DepartmentforCongenitalDisorders,StatensSerumInstitut,42Copenhagen,DK4336DepartmentofPsychiatry,WeillCornellMedicalCollege,NewYork,NY,US4437DepartmentofPsychiatryandPsychotherapy,UniversityHospitalCarlGustavCarus,Technische45UniversitätDresden,Dresden,DE4638DepartmentofMedicalEpidemiologyandBiostatistics,KarolinskaInstitutet,Stockholm,SE4739DepartmentofPsychiatricResearch,DiakonhjemmetHospital,Oslo,NO4840Psychiatry,UMCUtrechtHersencentrumRudolfMagnus,Utrecht,NL4941HumanGenetics,UniversityofCaliforniaLosAngeles,LosAngeles,CA,US5042InstituteofPsychiatricPhenomicsandGenomics(IPPG),UniversityHospital,LMUMunich,Munich,DE51
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
43DepartmentofPsychiatryandHumanBehavior,UniversityofCalifornia,Irvine,Irvine,CA,US144Molecular&BehavioralNeuroscienceInstituteandDepartmentofComputationalMedicine&2Bioinformatics,UniversityofMichigan,AnnArbor,MI,US345Psychiatry,UniversityofCaliforniaSanFrancisco,SanFrancisco,CA,US446InstitutodeSaludCarlosIII,BiomedicalNetworkResearchCentreonMentalHealth(CIBERSAM),5Madrid,ES647DepartmentofPsychiatry,HospitalUniversitariValld´Hebron,Barcelona,ES748DepartmentofPsychiatryandForensicMedicine,UniversitatAutònomadeBarcelona,Barcelona,ES849PsychiatricGeneticsUnit,GroupofPsychiatryMentalHealthandAddictions,Valld´HebronResearch9Institut(VHIR),UniversitatAutònomadeBarcelona,Barcelona,ES1050DepartmentofPsychiatry,MoodDisordersProgram,McGillUniversityHealthCenter,Montreal,QC,CA1151DivisionofPsychiatry,UniversityofEdinburgh,Edinburgh,GB1252UniversityofIowaHospitalsandClinics,IowaCity,IA,US1353TranslationalGenomics,USC,Phoenix,AZ,US1454DepartmentofTranslationalResearchinPsychiatry,MaxPlanckInstituteofPsychiatry,Munich,DE1555CentreforPsychiatry,QueenMaryUniversityofLondon,London,GB1656UCLGeneticsInstitute,UniversityCollegeLondon,London,GB1757DepartmentofPsychiatry,LaboratoryofPsychiatricGenetics,PoznanUniversityofMedicalSciences,18Poznan,PL1958DepartmentofNeurosciences,UniversityofCaliforniaSanDiego,LaJolla,CA,US2059DepartmentofRadiology,UniversityofCaliforniaSanDiego,LaJolla,CA,US2160DepartmentofPsychiatry,UniversityofCaliforniaSanDiego,LaJolla,CA,US2261DepartmentofCognitiveScience,UniversityofCaliforniaSanDiego,LaJolla,CA,US2362AppliedMolecularGenomicsUnit,VIBDepartmentofMolecularGenetics,UniversityofAntwerp,24Antwerp,Belgium2563DepartmentofPsychiatryandBehavioralSciences,JohnsHopkinsUniversitySchoolofMedicine,26Baltimore,MD,US2764DepartmentofMedicalGenetics,OsloUniversityHospitalUllevål,Oslo,NO2865NORMENT,KGJebsenCentreforPsychosisResearch,DepartmentofClinicalScience,Universityof29Bergen,Bergen,NO3066DepartmentofNeurology,OsloUniversityHospital,Oslo,NO3167NORMENT,KGJebsenCentreforPsychosisResearch,OsloUniversityHospital,Oslo,NO3268CenterforStatisticalGeneticsandDepartmentofBiostatistics,UniversityofMichigan,AnnArbor,MI,33US3469DepartmentofMedical&MolecularGenetics,IndianaUniversity,Indianapolis,IN,US3570DepartmentofGeneticEpidemiologyinPsychiatry,CentralInstituteofMentalHealth,MedicalFaculty36Mannheim,HeidelbergUniversity,Mannheim,DE3771CenterforNeurobehavioralGenetics,UniversityofCaliforniaLosAngeles,LosAngeles,CA,US3872DepartmentofMolecularMedicineandSurgery,KarolinskaInstitutetandCenterforMolecular39Medicine,KarolinskaUniversityHospital,Stockholm,SE4073DepartmentofClinicalNeuroscience,KarolinskaInstitutetandCenterforMolecularMedicine,41KarolinskaUniversityHospital,Stockholm,SE4274ChildandAdolescentPsychiatryResearchCenter,Stockholm,SE4375DepartmentofPsychiatryandPsychotherapy,UniversityMedicalCenterGöttingen,Göttingen,DE4476DepartmentofPsychiatry,DalhousieUniversity,Halifax,NS,CA4577GeneticsandComputationalBiology,QIMRBerghoferMedicalResearchInstitute,Brisbane,QLD,AU4678DepartmentofPsychologicalMedicine,UniversityofWorcester,Worcester,GB4779SchoolofBiomedicalandHealthcareSciences,PlymouthUniversityPeninsulaSchoolsofMedicineand48Dentistry,Plymouth,GB4980SchoolofPsychiatry,UniversityofNewSouthWales,Sydney,NSW,AU5081BioinformaticsResearchCentre,AarhusUniversity,Aarhus,DK5182Biostatistics,UniversityofMinnesotaSystem,Minneapolis,MN,US5283MentalHealthDepartment,UniversityRegionalHospital,BiomedicineInstitute(IBIMA),Málaga,ES53
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
84DepartmentofPsychology,EberhardKarlsUniversitätTübingen,Tubingen,DE185DepartmentofPsychiatryandBehavioralSciences,HowardUniversityHospital,Washington,DC,US286CenterforMultimodalImagingandGenetics,UniversityofCaliforniaSanDiego,LaJolla,CA,US387PsychiatrieTranslationnelle,InsermU955,Créteil,FR488FacultédeMédecine,UniversitéParisEst,Créteil,FR589CampbellFamilyMentalHealthResearchInstitute,CentreforAddictionandMentalHealth,Toronto,6ON,CA790NeurogeneticsSection,CentreforAddictionandMentalHealth,Toronto,ON,CA891DepartmentofPsychiatry,UniversityofToronto,Toronto,ON,CA992InstituteofMedicalSciences,UniversityofToronto,Toronto,ON,CA1093DepartmentofPsychiatry,PsychosomaticMedicineandPsychotherapy,UniversityHospitalFrankfurt,11FrankfurtamMain,DE1294CellBiology,SUNYDownstateMedicalCenterCollegeofMedicine,Brooklyn,NY,US1395InstituteforGenomicHealth,SUNYDownstateMedicalCenterCollegeofMedicine,Brooklyn,NY,US1496CenterforResearchinEnvironmentalEpidemiology(CREAL),Barcelona,ES1597Psychiatry,Altrecht,Utrecht,NL1698Psychiatry,GGZinGeest,Amsterdam,NL1799Psychiatry,VUmedischcentrum,Amsterdam,NL18100Psychiatry,NorthEastLondonNHSFoundationTrust,Ilford,GB19101ClinicforPsychiatryandPsychotherapy,UniversityHospitalCologne,Cologne,DE20102PsychiatricandNeurodevelopmentalGeneticsUnit,MassachusettsGeneralHospital,Boston,MA,US21103HudsonAlphaInstituteforBiotechnology,Huntsville,AL,US22104DepartmentofHumanGenetics,UniversityofMichigan,AnnArbor,MI,US23105Psychiatry,UniversityofIllinoisatChicagoCollegeofMedicine,Chicago,IL,US24106MaxPlanckInstituteofPsychiatry,Munich,DE25107MentalHealth,NHS24,Glasgow,GB26108DivisionofPsychiatry,CentreforClinicalBrainSciences,UniversityofEdinburgh,Edinburgh,GB27109Psychiatry,BrighamandWomen'sHospital,Boston,MA,US28110DepartmentofPsychiatryandPsychotherapy,UniversityofBonn,Bonn,DE29111DepartmentofGenetics,HarvardMedicalSchool,Boston,MA,US30112DepartmentofPsychiatry,UniversityofMichigan,AnnArbor,MI,US31113GeneticCancerSusceptibilityGroup,InternationalAgencyforResearchonCancer,Lyon,FR32114EstonianGenomeCenter,UniversityofTartu,Tartu,EE33115DisciplineofBiochemistry,NeuroimagingandCognitiveGenomics(NICOG)Centre,National34UniversityofIreland,Galway,Galway,IE35116NeuropsychiatricGeneticsResearchGroup,DeptofPsychiatryandTrinityTranslationalMedicine36Institute,TrinityCollegeDublin,Dublin,IE37117InstituteofNeuroscienceandMedicine(INM-1),ResearchCentreJülich,Jülich,DE38118Research/Psychiatry,VeteransAffairsSanDiegoHealthcareSystem,SanDiego,CA,US39119DepartmentofClinicalSciences,Psychiatry,UmeåUniversityMedicalFaculty,Umeå,SE40120DepartmentofClinicalPsychiatry,PsychiatryClinic,ClinicalCenterUniversityofSarajevo,Sarajevo,41BA42121DepartmentofNeurobiology,Caresciences,andSociety,KarolinskaInstitutetandCenterfor43MolecularMedicine,KarolinskaUniversityHospital,Stockholm,SE44122Psychiatry,HarvardMedicalSchool,Boston,MA,US45123DivisionofClinicalResearch,MassachusettsGeneralHospital,Boston,MA,US46124OutpatientClinicforBipolarDisorder,Altrecht,Utrecht,NL47125DepartmentofPsychiatry,WashingtonUniversityinSaintLouis,SaintLouis,MO,US48126DepartmentofBiochemistryandMolecularBiologyII,InstituteofNeurosciences,Centerfor49BiomedicalResearch,UniversityofGranada,Granada,ES50127DepartmentofNeuroscience,IcahnSchoolofMedicineatMountSinai,NewYork,NY,US51128Medicine,Psychiatry,BiomedicalInformatics,VanderbiltUniversityMedicalCenter,Nashville,TN,US52129DepartmentofHealthSciencesResearch,MayoClinic,Rochester,MN,US53
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
130PsychiatryandBehavioralSciences,StanfordUniversitySchoolofMedicine,Stanford,CA,US1131RushUniversityMedicalCenter,Chicago,IL,US2132ScrippsTranslationalScienceInstitute,LaJolla,CA,US3133NeuroscienceResearchAustralia,Sydney,NSW,AU4134FacultyofMedicine,DepartmentofPsychiatry,SchoolofHealthSciences,UniversityofIceland,5Reykjavik,IS6135DivMentalHealthandAddiction,OsloUniversityHospital,Oslo,NO7136NORMENT,UniversityofOslo,Oslo,NO8137PsychiatryandtheBehavioralSciences,UniversityofSouthernCalifornia,LosAngeles,CA,US9138MoodDisorders,PsyQ,Rotterdam,NL10139InstituteforMedicalSciences,UniversityofAberdeen,Aberdeen,UK11140ResearchDivision,FederalInstituteforDrugsandMedicalDevices(BfArM),Bonn,DE12141CentreforAddictionandMentalHealth,Toronto,ON,CA13142Neurogenomics,TGen,LosAngeles,AZ,US14143Psychiatry,PsychiatrischesZentrumNordbaden,Wiesloch,DE15144ComputationalSciencesCenterofEmphasis,PfizerGlobalResearchandDevelopment,Cambridge,16MA,US17145DepartmentofBiostatistics,PrincessMargaretCancerCentre,Toronto,ON,CA18146DallaLanaSchoolofPublicHealth,UniversityofToronto,Toronto,ON,CA19147PsychologicalMedicine,InstituteofPsychiatry,Psychology&Neuroscience,King'sCollegeLondon,20London,GB21148DepartmentofMentalHealth,JohnsHopkinsUniversityBloombergSchoolofPublicHealth,22Baltimore,MD,US23149InstituteofGeneticMedicine,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,US24150NORMENT,KGJebsenCentreforPsychosisResearch,DivisionofMentalHealthandAddiction,25InstituteofClinicalMedicineandDiakonhjemmetHospital,UniversityofOslo,Oslo,NO26151NationalInstituteofMentalHealth,Klecany,CZ27152DisciplineofPsychiatry,UniversityofAdelaide,Adelaide,SA,AU28153DepartmentofPsychiatryandAddictionMedicine,AssistancePublique-HôpitauxdeParis,Paris,FR29154ParisBipolarandTRDExpertCentres,FondaMentalFoundation,Paris,FR30155UMR-S1144Team1:Biomarkersofrelapseandtherapeuticresponseinaddictionandmood31disorders,INSERM,Paris,FR32156Psychiatry,UniversitéParisDiderot,Paris,FR33157Psychiatry,UniversityofPennsylvania,Philadelphia,PA,US34158DepartmentofPsychiatry,UniversityofMünster,Münster,DE35159DivisionofEndocrinology,Children'sHospitalBoston,Boston,MA,US36160CentreforAffectiveDisorders,InstituteofPsychiatry,PsychologyandNeuroscience,London,GB37161DepartmentofPsychiatry&Psychology,MayoClinic,Rochester,MN,US38162SchoolofMedicalSciences,UniversityofNewSouthWales,Sydney,NSW,AU39163DepartmentofHumanGenetics,UniversityofChicago,Chicago,IL,US40164BiometricPsychiatricGeneticsResearchUnit,AlexandruObregiaClinicalPsychiatricHospital,41Bucharest,RO42165InstituteofNeuroscienceandPhysiology,UniversityofGothenburg,Gothenburg,SE43166INSERM,Paris,FR44167DepartmentofMedical&MolecularGenetics,King'sCollegeLondon,London,GB45168NeuroscienceTherapeuticArea,JanssenResearchandDevelopment,LLC,Titusville,NJ,US46169CancerEpidemiologyandPrevention,M.Sklodowska-CurieCancerCenterandInstituteofOncology,47Warsaw,PL48170SchoolofPsychology,TheUniversityofQueensland,Brisbane,QLD,AU49171ResearchInstitute,LindnerCenterofHOPE,Mason,OH,US50172CentreforCognitiveAgeingandCognitiveEpidemiology,UniversityofEdinburgh,Edinburgh,GB51173HumanGeneticsBranch,IntramuralResearchProgram,NationalInstituteofMentalHealth,Bethesda,52MD,US53
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
174DivisionofMentalHealthandAddiction,OsloUniversityHospital,Oslo,NO1175DivisionofMentalHealthandAddiction,UniversityofOslo,InstituteofClinicalMedicine,Oslo,NO2176InstituteofMolecularandCellBiology,UniversityofTartu,Tartu,EE3177MentalHealth,FacultyofMedicineandHealthSciences,NorwegianUniversityofScienceand4Technology-NTNU,Trondheim,NO5178Psychiatry,StOlavsUniversityHospital,Trondheim,NO6179PsychosisResearchUnit,AarhusUniversityHospital,Risskov,DK7180MunichClusterforSystemsNeurology(SyNergy),Munich,DE8181UniversityofLiverpool,Liverpool,GB9182PsychiatryandHumanGenetics,UniversityofPittsburgh,Pittsburgh,PA,US10183MentalHealthServicesintheCapitalRegionofDenmark,MentalHealthCenterCopenhagen,11UniversityofCopenhagen,Copenhagen,DK12184DivisionofPsychiatry,HaukelandUniversitetssjukehus,Bergen,NO13185FacultyofMedicineandDentistry,UniversityofBergen,Bergen,NO14186HumanGeneticsandComputationalBiomedicine,PfizerGlobalResearchandDevelopment,Groton,15CT,US16187CollegeofMedicineInstituteforGenomicHealth,SUNYDownstateMedicalCenterCollegeof17Medicine,Brooklyn,NY,US18188DepartmentofClinicalGenetics,AmsterdamNeuroscience,VrijeUniversiteitMedicalCenter,19Amsterdam,NL20189DepartmentofNeurologyandNeurosurgery,McGillUniversity,FacultyofMedicine,Montreal,QC,CA21190MontrealNeurologicalInstituteandHospital,Montreal,QC,CA22191DepartmentofBiomedicalandNeuroMotorSciences,UniversityofBologna,Bologna,IT23192DepartmentofPsychiatry,MassachusettsGeneralHospital,Boston,MA,US24193PsychiatricandNeurodevelopmentalGeneticsUnit(PNGU),MassachusettsGeneralHospital,Boston,25MA,US26194FacultyofMedicine,UniversityofIceland,Reykjavik,IS27195DepartmentofPsychiatry,HospitalNamsos,Namsos,NO28196DepartmentofNeuroscience,NorgesTekniskNaturvitenskapeligeUniversitetFakultetfor29naturvitenskapogteknologi,Trondheim,NO30197DepartmentofGenetics,UniversityofNorthCarolinaatChapelHill,ChapelHill,NC,US31198DepartmentofPsychiatry,UniversityofNorthCarolinaatChapelHill,ChapelHill,NC,US32199DepartmentofPsychiatry,McGillUniversity,Montreal,QC,CA33200DeptofPsychiatry,SanktOlavsHospitalUniversitetssykehusetiTrondheim,Trondheim,NO34201ClinicalInstituteofNeuroscience,HospitalClinic,UniversityofBarcelona,IDIBAPS,CIBERSAM,35Barcelona,ES36202InstituteofBiologicalPsychiatry,MHCSct.Hans,MentalHealthServicesCopenhagen,Roskilde,DK37203DepartmentofClinicalMedicine,UniversityofCopenhagen,Copenhagen,DK38204Psychiatry,IndianaUniversitySchoolofMedicine,Indianapolis,IN,US39205BiochemistryandMolecularBiology,IndianaUniversitySchoolofMedicine,Indianapolis,IN,US4041424344 45
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
Funding:1Study Leadinvestigator Country,Funder,Awardnumber
PGC PSullivan USA,NIMHMH109528
PGC DPosthuma Netherlands,ScientificOrganizationNetherlands,480-05-003
PGC DPosthuma DutchBrainFoundationandtheVUUniversityAmsterdamNetherlands
Analysis,UK-BDRN(Cardiff) PAHolmans MedicalResearchCouncil(MRC)Centre(G0801418)andProgramGrants(G0800509)
Analysis NRWray NHMRC1078901,108788
BACCS GBreen GB,JRIC,HG,CLweresupportedinpartbytheNIHRMaudsleyBiomedicalResearchCentre(‘BRC’)hostedatKing’sCollegeLondonandSouthLondonandMaudsleyNHSFoundationTrust,andfundedbytheNationalInstituteforHealthResearchunderitsBiomedicalResearchCentresfundinginitiative.
BD_TRS UDannlowski Germany,DFG,GrantFOR2107DA1151/5-1;GrantSFB-TRR58,ProjectC09
BiGS,Uchicago ESGershon R01MH103368
BiGS,NIMH FJMcMahon US,NIMH,R01MH061613,ZIAMH002843
BiGS,GAIN,UCSD JKelsoe US,NIMH,MH078151,MH081804,MH59567
BiGS,UniversityofPittsburgh VNimgaonkar US,NIMHMH63480
BOMA-Australia JMFullerton Australia,NationalHealthandMedicalResearchCouncil,grantnumbers:1037196;1066177;1063960
BOMA-Australia SEMedland Australia,NationalHealthandMedicalResearchCouncil,grantnumbers:1103623
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
BOMA-Australia PBMitchell Australia,NationalHealthandMedicalResearchCouncil,grantnumbers:1037196
BOMA-Australia GWMontgomery Australia,NationalHealthandMedicalResearchCouncil,grantnumbers:1078399
BOMA-Australia PRSchofield Australia,NationalHealthandMedicalResearchCouncil,grantnumbers:1037196
BOMA-Romania MGrigoroiu-Serbanescu Romania,UEFISCDI,Grantno.89/2012
BOMA-GermanyI,II,III SCichon Germany,BMBFIntegrament,01ZX1314A/01ZX1614A
BOMA-GermanyI,II,III SCichon Germany,BMBFNGFNplusMooDS,01GS08144
BOMA-GermanyI,II,III SCichon Switzerland,SNSF,156791
BOMA-GermanyI,II,III MMNöthen Germany,BMBFIntegrament,01ZX1314A/01ZX1614A
BOMA-GermanyI,II,III MMNöthen Germany,BMBFNGFNplusMooDS,01GS08144
BOMA-GermanyI,II,III MMNöthen Germany,DeutscheForschungsgemeinschaft,ExcellenceClusterImmunoSensation
BOMA-GermanyI,II,III MMNöthen Germany,DeutscheForschungsgemeinschaft,NO246/10-1
BOMA-GermanyI,II,III SHWitt Germany,DeutscheForschungsgemeinschaft,WI3429/3-1
BOMA-GermanyI,II,III,BOMA-Spain
MRietschel Germany,BMBFIntegrament,01ZX1314G/01ZX1614G
BOMA-GermanyI,II,III,BOMA-Spain
MRietschel Germany,BMBFNGFNplusMooDS,01GS08147
BOMA-GermanyI,II,III,BOMA-Spain
MRietschel Germany,DeutscheForschungsgemeinschaft,RI908/11-1
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
BOMA-GermanyI,II,III,PsyCourse,BiGS
TGSchulze Germany,BMBFIntegrament,01ZX1314K
BOMA-GermanyI,II,III,PsyCourse,BiGS
TGSchulze Germany,DFG,SCHU1603/4-1,SCHU1603/5-1,SCHU1603/7-1
BOMA-GermanyI,II,III,PsyCourse,BiGS
TGSchulze Germany,Dr.Lisa-OehlerFoundation(Kassel,Germany)
BulgarianTrios(Cardiff) GKirov TherecruitmentwasfundedbytheJanssenResearchFoundation.GenotypingwasfundedbymultiplegrantstotheStanleyCenterforPsychiatricResearchattheBroadInstitutefromtheStanleyMedicalResearchInstitute,TheMerckGenomeResearchFoundation,andtheHermanFoundation.
Fran MLeboyer France,Inserm,ANR
Halifax MAlda CIHRgrant#64410
iPSYCHBPgroup ADBørglum Denmark,LundbeckFoundation,R102-A9118andR155-2014-1724(iPSYCH)
iPSYCHBPgroup ADBørglum Denmark,AarhusUniversity,iSEQandCIRRAU
iPSYCHBPgroup ADBørglum USA,StanleyMedicalResearchInstitute
iPSYCHBPgroup ADBørglum EU,EuropeanResearchCouncil,294838
MayoBipolarDisorderBiobank JMBiernacka,MAFrye MarriotFoundationandtheMayoClinicCenterforIndividualizedMedicine
Michigan MBoehnke US,NIMH,R01MH09414501A1;US,NIMH,MH105653
MountSinai EAStahl NARSADYoungInvestigatorAward
MountSinai,STEP-BD,FAST PSklar,EAStahl USNIHR01MH106531,R01MH109536
NeuRA-CASSI-Australia CShannonWeickert Australia,NationalHealthandMedicalResearchCouncil,grantnumber:568807
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
NeuRA-CASSI-Australia TWWeickert Australia,NationalHealthandMedicalResearchCouncil,grantnumber:568807
NeuRA-IGP-Australia MJGreen Australia,NationalHealthandMedicalResearchCouncil,grantnumbers:630471,1081603
Norway IAgartz Sweden,SwedishResearchCouncil
Norway OAAndreassen Norway,ResearchCouncilofNorway(#217776,#223273,#248778,#249711),KGJebsenStiftelsen,TheSouth-EastNorwayRegionalHealthAuthority(#2012-132,#2012-131,#2017-004)
Norway TElvsåshagen Norway,TheSouth-EastNorwayRegionalHealthAuthority(#2015-078)andaresearchgrantfromMrs.Throne-Holst.
Norway IMelle Norway,ResearchCouncilofNorway(#421716,#223273),KGJebsenStiftelsen,TheSouth-EastNorwayRegionalHealthAuthority(#2011085,#2013088,#2014102)
Norway KJOedegaard Norway,theWesternNorwayRegionalHealthAuthority
Norway OBSmeland Norway,TheSouth-EastNorwayRegionalHealthAuthority(#2016-064,#2017-004)
Span2 MRibasés Spain,InstitutodeSaludCarlosIII,MinisteriodeEconomía,IndustriayCompetitividad,CP09/00119andCPII15/00023
Span2 CSánchez-Mora Spain,InstitutodeSaludCarlosIII,MinisteriodeEconomía,IndustriayCompetitividad,CD15/00199andMV16/00039
StateUniversityofNewYork,DownstateMedicalCenter(SUNYDMC)
CPato,MTPato,JAKnowles,HMedeiros
US,NationalInstitutesofHealth,R01MH085542
SWEBIC MLandén TheStanleyCenterforPsychiatricResearch,BroadInstitutefromagrantfromStanleyMedicalResearchInstitute;NIMHMH077139(PFS),TheSwedishResearchCouncil(K2014-62X-14647-12-51andK2010-61P-21568-01-4),andtheSwedishfoundationforStrategicResearch(KF10-0039)
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
UCL AMcQuillin MedicalResearchCouncil(MRC)-G1000708
UCLA-Utrecht(LosAngeles) NBFreimer US,NationalInstitutesofHealth,R01MH090553,U01MH105578
UCLA-Utrecht(LosAngeles) LMOldeLoohuis US,NationalInstitutesofHealth,R01MH090553,U01MH105578
UCLA-Utrecht(LosAngeles) RAOphoff US,NationalInstitutesofHealth,R01MH090553,U01MH105578
UCLA-Utrecht(LosAngeles) APSOri US,NationalInstitutesofHealth,R01MH090553,U01MH105578
UK-BDRN(Cardiff) MCO'Donovan MedicalResearchCouncil(MRC)Centre(G0801418)andProgramGrants(G0800509)
UK-BDRN(Cardiff) MJOwen MedicalResearchCouncil(MRC)Centre(G0801418)andProgramGrants(G0800509)
UK-BDRN(Cardiff) NCraddock,IJones,LAJones
UK,WellcomeTrust,078901;USA,StanleyMedicalResearchInstitute,5710002223-01
UK-BDRN(Cardiff) ADiFlorio EuropeanCommissionMarieCurieFellowship,grantnumber623932.
UNIBO/UniversityofBarcelona,HospitalClinic,IDIBAPS,CIBERSAM
EVieta GrantsPI15/00283(Spain)and2014SGR398(Catalonia)
USC JLSobell USA,NationalInstitutesofHealth,R01MH085542
WTCCC NCraddock;AHYoung TheprincipalfunderofthisprojectwastheWellcomeTrust.Forthe1958BirthCohort,venousbloodcollectionwasfundedbytheUKMedicalResearchCouncil.AHYwasfundedbyNIMH(USA);CIHR(Canada);NARSAD(USA);StanleyMedicalResearchInstitute(USA);MRC(UK);WellcomeTrust(UK);RoyalCollegeofPhysicians(Edin);BMA(UK);UBC-VGHFoundation(Canada);WEDC(Canada);CCSDepressionResearchFund(Canada);MSFHR(Canada);NIHR(UK);Janssen(UK)
1
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
Acknowledgments:1
ThispaperisdedicatedtothememoryofPsychiatricGenomicsConsortium(PGC)founding2
memberandBipolardisorderworkinggroupco-chairPamelaSklar.Wearedeeplyindebtedto3
theinvestigatorswhocomprisethePGC,andtothesubjectswhohavesharedtheirlife4
experienceswithPGCinvestigators.ThePGChasreceivedmajorfundingfromtheUSNational5
InstituteofMentalHealth(PGC3:U01MH109528,PGC2:U01MH094421,PGC1:U016
MH085520).StatisticalanalyseswerecarriedoutontheNLGeneticClusterComputer7
(http://www.geneticcluster.org)hostedbySURFsara.8
BACCS:ThisworkwassupportedinpartbytheNIHRMaudsleyBiomedicalResearchCentre9
(‘BRC’)hostedatKing’sCollegeLondonandSouthLondonandMaudsleyNHSFoundationTrust,10
andfundedbytheNationalInstituteforHealthResearchunderitsBiomedicalResearchCentres11
fundinginitiative.Theviewsexpressedarethoseoftheauthorsandnotnecessarilythoseofthe12
BRC,theNHS,theNIHRortheDepartmentofHealthorKing’sCollegeLondon.Wegratefully13
acknowledgecapitalequipmentfundingfromtheMaudsleyCharity(GrantReference980)and14
Guy’sandStThomas’sCharity(GrantReferenceSTR130505).15
BD_TRS:ThisworkwasfundedbytheGermanResearchFoundation(DFG,grantFOR210716
DA1151/5-1toUD;SFB-TRR58,ProjectC09toUD)andtheInterdisciplinaryCenterforClinical17
Research(IZKF)ofthemedicalfacultyofMünster(grantDan3/012/17toUD).18
BiGS,GAIN:FJMwassupportedbytheNIMHIntramuralResearchProgram,NIH,DHHS.19
BOMA-Australia:JMFwouldliketothankJanetteMO'NeilandBettyCLynchfortheirsupport.20
BOMA-GermanyI,BOMA-GermanyII,BOMA-GermanyIII,PsyCourse:Thisworkwassupported21
bytheGermanMinistryforEducationandResearch(BMBF)throughtheIntegratedNetwork22
IntegraMent(IntegratedUnderstandingofCausesandMechanismsinMentalDisorders),under23
theauspicesofthee:Medprogram(grant01ZX1314A/01ZX1614AtoMMNandSC,grant24
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
01ZX1314G/01ZX1614GtoMR,grant01ZX1314KtoTGS).Thisworkwassupportedbythe1
GermanMinistryforEducationandResearch(BMBF)grantsNGFNplusMooDS(Systematic2
InvestigationoftheMolecularCausesofMajorMoodDisordersandSchizophrenia;grant3
01GS08144toMMNandSC,grant01GS08147toMR).Thisworkwasalsosupportedbythe4
DeutscheForschungsgemeinschaft(DFG),grantNO246/10-1toMMN(FOR2107),grantRI5
908/11-1toMR(FOR2107),grantWI3429/3-1toSHW,grantsSCHU1603/4-1,SCHU1603/5-16
(KFO241)andSCHU1603/7-1(PsyCourse)toTGS.ThisworkwassupportedbytheSwiss7
NationalScienceFoundation(SNSF,grant156791toSC).MMNissupportedthroughthe8
ExcellenceClusterImmunoSensation.TGSissupportedbyanunrestrictedgrantfromtheDr.9
Lisa-OehlerFoundation.AJFreceivedsupportfromtheBONFORProgrammeoftheUniversityof10
Bonn,Germany.MHwassupportedbytheDeutscheForschungsgemeinschaft.11
Edinburgh:DJMissupportedbyanNRSClinicalFellowshipfundedbytheCSO.12
Fran:ThisresearchwassupportedbyFoundationFondaMental,Créteil,Franceandbythe13
Investissementsd’AvenirProgramsmanagedbytheANRunderreferencesANR-11-IDEX-0004-14
02andANR-10-COHO-10-01.15
Halifax:HalifaxdatawereobtainedwithsupportfromtheCanadianInstitutesofHealth16
Research.17
iPSYCHBPgroup:ADBandtheiPSYCHteamacknowledgesfundingfromTheLundbeck18
Foundation(grantnoR102-A9118andR155-2014-1724),theStanleyMedicalResearchInstitute,19
anAdvancedGrantfromtheEuropeanResearchCouncil(projectno:294838),andgrantsfrom20
AarhusUniversitytotheiSEQandCIRRAUcenters.21
TheMayoBipolarDisorderBiobankwasfundedbytheMarriotFoundationandtheMayoClinic22
CenterforIndividualizedMedicine23
Michigan(NIMH/PritzkerNeuropsychiatricDisordersResearchConsortium):Wethankthe24
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
participantswhodonatedtheirtimeandDNAtomakethisstudypossible.Wethankmembers1
oftheNIMHHumanGeneticsInitiativeandtheUniversityofMichiganPrechterBipolarDNA2
RepositoryforgenerouslyprovidingphenotypedataandDNAsamples.Manyoftheauthorsare3
membersofthePritzkerNeuropsychiatricDisordersResearchConsortiumwhichissupportedby4
thePritzkerNeuropsychiatricDisordersResearchFundL.L.C.Asharedintellectualproperty5
agreementexistsbetweenthisphilanthropicfundandtheUniversityofMichigan,Stanford6
University,theWeillMedicalCollegeofCornellUniversity,HudsonAlphaInstituteof7
Biotechnology,theUniversitiesofCaliforniaatDavis,andatIrvine,toencouragethe8
developmentofappropriatefindingsforresearchandclinicalapplications.9
MountSinai:ThisworkwasfundedinpartbyaNARSADYoungInvestigatorawardtoEAS.10
NeuRA-CASSI-Australia:ThisworkwasfundedbytheNSWMinistryofHealth,OfficeofHealth11
andMedicalResearch.CSWwasarecipientofNationalHealthandMedicalResearchCouncil12
(Australia)Fellowships(#1117079,#1021970).13
NeuRA-IGP-Australia:MJGwassupportedbyaNHMRCCareerDevelopmentFellowship14
(1061875).15
Norway:TEwasfundedbyTheSouth-EastNorwayRegionalHealthAuthority(#2015-078)anda16
researchgrantfromMrs.Throne-Holst.17
Span2:CSMisarecipientofaSaraBorrellcontract(CD15/00199)andamobilitygrant18
(MV16/00039)fromtheInstitutodeSaludCarlosIII,MinisteriodeEconomía,Industriay19
Competitividad,Spain.MRisarecipientofaMigueldeServetcontract(CP09/00119and20
CPII15/00023)fromtheInstitutodeSaludCarlosIII,MinisteriodeEconomía,Industriay21
Competitividad,Spain.ThisinvestigationwassupportedbyInstitutodeSaludCarlosIII22
(PI12/01139,PI14/01700,PI15/01789,PI16/01505),andcofinancedbytheEuropeanRegional23
DevelopmentFund(ERDF),AgènciadeGestiód’AjutsUniversitarisideRecerca-AGAUR,24
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
GeneralitatdeCatalunya(2014SGR1357),DepartamentdeSalut,GeneralitatdeCatalunya,1
Spain,andaNARSADYoungInvestigatorGrantfromtheBrain&BehaviorResearchFoundation.2
ThisprojecthasalsoreceivedfundingfromtheEuropeanUnion’sHorizon2020Researchand3
InnovationProgrammeunderthegrantagreementsNo667302and643051.4
SWEBIC:Wearedeeplygratefulfortheparticipationofallsubjectscontributingtothisresearch,5
andtothecollectionteamthatworkedtorecruitthem.WealsowishtothanktheSwedish6
NationalQualityRegisterforBipolarDisorders:BipoläR.Fundingsupportwasprovidedbythe7
StanleyCenterforPsychiatricResearch,BroadInstitutefromagrantfromStanleyMedical8
ResearchInstitute,theSwedishResearchCouncil,andtheNIMH.9
Sweden:ThisworkwasfundedbytheSwedishResearchCouncil(M.Schalling,C.Lavebratt),the10
StockholmCountyCouncil(M.Schalling,C.Lavebratt,L.Backlund,L.Frisén,U.Ösby)andthe11
SöderströmFoundation(L.Backlund).12
UK-BDRN:BDRNwouldliketoacknowledgefundingfromtheWellcomeTrustandStanley13
MedicalResearchInstitute,andespeciallytheresearchparticipantswhocontinuetogivetheir14
timetoparticipateinourresearch.15
UNIBO/UniversityofBarcelona,HospitalClinic,IDIBAPS,CIBERSAM:EVthanksthesupportof16
theSpanishMinistryofEconomyandCompetitiveness(PI15/00283)integratedintothePlan17
NacionaldeI+D+IycofinanciadoporelISCIII-SubdirecciónGeneraldeEvaluaciónyelFondo18
EuropeodeDesarrolloRegional(FEDER);CIBERSAM;andtheComissionatperaUniversitatsi19
RecercadelDIUEdelaGeneralitatdeCatalunyatotheBipolarDisordersGroup(2014SGR398).20
WTCCC:TheprincipalfunderofthisprojectwastheWellcomeTrust.Forthe1958BirthCohort,21
venousbloodcollectionwasfundedbytheUKMedicalResearchCouncil.22
AHYisfundedbytheNationalInstituteforHealthResearch(NIHR)BiomedicalResearchCentre23
atSouthLondonandMaudsleyNHSFoundationTrustandKing’sCollegeLondon.Theviews24
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
expressedarethoseoftheauthorsandnotnecessarilythoseoftheNHS,theNIHR,orthe1
DepartmentofHealth.2
3
ConflictsofInterest:4
T.E.Thorgeirsson,S.Steinberg,H.StefanssonandK.StefanssonareemployedbydeCODE5
Genetics/Amgen.Multipleadditionalauthorsworkforpharmaceuticalorbiotechnology6
companiesinamannerdirectlyanalogoustoacademicco-authorsandcollaborators.A.H.Young7
hasgivenpaidlecturesandisonadvisoryboardsforthefollowingcompanieswithdrugsusedin8
affectiveandrelateddisorders:Astrazenaca,EliLilly,Janssen,Lundbeck,Sunovion,Servier,9
Livanova.A.H.YoungisLeadInvestigatorforEmboldenStudy(Astrazenaca),BCINeuroplasticity10
studyandAripiprazoleManiaStudy,whichareinvestigator-initiatedstudiesfromAstrazenaca,11
EliLilly,Lundbeck,andWyeth.J.NurnbergerisaninvestigatorforJanssen.P.F.Sullivanreports12
thefollowingpotentiallycompetingfinancialinterests:Lundbeck(advisorycommittee),Pfizer13
(ScientificAdvisoryBoardmember),andRoche(grantrecipient,speakerreimbursement).G.14
BreenreportsconsultancyandspeakerfeesfromEliLillyandIlluminaandgrantfundingfromEli15
Lilly.O.A.AndreassenhasreceivedspeakerfeesfromLundbeck.Allotherauthorsdeclareno16
financialinterestsorpotentialconflictsofinterest.17
18
19
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
DISPLAYITEMS(inlineaboveinthismanuscriptversion):1
Figure1.Manhattanplotforourprimarygenomewideassociationanalysisof20,352casesand2
31,358controls.GWAS-log10P-valuesareplottedforallSNPsacrosschromosomes1-223
(diamonds,greenforlociwithleadSNPGWASP<10-6).CombinedGWAS+followup-log10P-4
valuesforleadSNPsreachinggenome-widesignificanceineitherGWASorcombinedanalysis5
(triangles,invertedifGWAS+followup-log10P>GWAS-log10P).Labelscorrespondtogene6
symbolspreviouslyreportedforpublishedloci(black)andthenearestgenesfornovelloci7
(blue),attopifGWAS+followupP<5x10-8.8
Table1.Genome-widesignificantbipolardisorderriskloci.9
Figure2.AssociationofBD1andBD2subtypeswithschizophrenia(SCZ)andmajordepression10
(DEPR)polygenicriskscores(PRS).ShownaremeanPRSvalues(1s.e.errorbars),adjustedfor11
studyandancestrycovariatesandscaledtothePRSmeanandsdincontrolsubjects,inBD112
(red)andBD2(blue)cases,forincreasingsourceGWASP-valuethresholds(increasinggrey)as13
indicated.P-values(italics)testBD1vsBD2meanPRS,inlogisticregressionofcasesubtypeon14
PRSwithcovariates.ResultsaredetailedinSupplementaryTable10.15
16
.CC-BY 4.0 International licensecertified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which was notthis version posted January 24, 2018. . https://doi.org/10.1101/173062doi: bioRxiv preprint
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