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, 45 (9), 984-94

Genetic Relationship Between Five Psychiatric Disorders Estimated From Genome-Wide SNPs

Cross-Disorder Group of the Psychiatric Genomics ConsortiumS Hong LeeStephan RipkeBenjamin M NealeStephen V FaraoneShaun M PurcellRoy H PerlisBryan J MowryAnita ThaparMichael E GoddardJohn S WitteDevin AbsherIngrid AgartzHuda AkilFarooq AminOle A AndreassenAdebayo AnjorinRichard AnneyVerneri AnttilaDan E ArkingPhilip AshersonMaria H AzevedoLena BacklundJudith A BadnerAnthony J BaileyTobias BanaschewskiJack D BarchasMichael R BarnesThomas B BarrettNicholas BassAgatino BattagliaMichael BauerMònica BayésFrank BellivierSarah E BergenWade BerrettiniCatalina BetancurThomas BetteckenJoseph BiedermanElisabeth B BinderDonald W BlackDouglas H R BlackwoodCinnamon S BlossMichael BoehnkeDorret I BoomsmaGerome BreenRené BreuerRichard BruggemanPaul CormicanNancy G BuccolaJan K BuitelaarWilliam E BunneyJoseph D BuxbaumWilliam F ByerleyEnda M ByrneSian CaesarWiepke CahnRita M CantorMiguel CasasAravinda ChakravartiKimberly ChambertKhalid ChoudhurySven CichonC Robert CloningerDavid A CollierEdwin H CookHilary CoonBru CormandAiden CorvinWilliam H CoryellDavid W CraigIan W CraigJennifer CrosbieMichael L CuccaroDavid CurtisDarina CzamaraSusmita DattaGeraldine DawsonRichard DayEco J De GeusFranziska DegenhardtSrdjan DjurovicGary J DonohoeAlysa E DoyleJubao DuanFrank DudbridgeEftichia DuketisRichard P EbsteinHoward J EdenbergJosephine EliaSean EnnisBruno EtainAyman FanousAnne E FarmerI Nicol FerrierMatthew FlickingerEric FombonneTatiana ForoudJosef FrankBarbara FrankeChristine FraserRobert FreedmanNelson B FreimerChristine M FreitagMarion FriedlLouise FrisénLouise GallagherPablo V GejmanLyudmila GeorgievaElliot S GershonDaniel H GeschwindIna GieglingMichael GillScott D GordonKatherine Gordon-SmithElaine K GreenTiffany A GreenwoodDorothy E GriceMagdalena GrossDetelina GrozevaWeihua GuanHugh GurlingLieuwe De HaanJonathan L HainesHakon HakonarsonJoachim HallmayerSteven P HamiltonMarian L HamshereThomas F HansenAnnette M HartmannMartin HautzingerAndrew C HeathAnjali K HendersStefan HermsIan B HickieMaria HipolitoSusanne HoefelsPeter A HolmansFlorian HolsboerWitte J HoogendijkJouke-Jan HottengaChristina M HultmanVanessa HusAndrés IngasonMarcus IsingStéphane JamainEdward G JonesIan JonesLisa JonesJung-Ying TzengAnna K KählerRené S KahnRadhika KandaswamyMatthew C KellerJames L KennedyElaine KennyLindsey KentYunjung KimGeorge K KirovSabine M KlauckLambertus KleiJames A KnowlesMartin A KohliDaniel L KollerBettina KonteAnia KorszunLydia KrabbendamRobert KrasuckiJonna KuntsiPhoenix KwanMikael LandénNiklas LångströmMark LathropJacob LawrenceWilliam B LawsonMarion LeboyerDavid H LedbetterPhil H LeeTodd LenczKlaus-Peter LeschDouglas F LevinsonCathryn M LewisJun LiPaul LichtensteinJeffrey A LiebermanDan-Yu LinDon H LinszenChunyu LiuFalk W LohoffSandra K LooCatherine LordJennifer K LoweSusanne LucaeDonald J MacIntyrePamela A F MaddenElena MaestriniPatrik K E MagnussonPamela B MahonWolfgang MaierAnil K MalhotraShrikant M ManeChrista L MartinNicholas G MartinManuel MattheisenKeith MatthewsMorten MattingsdalSteven A McCarrollKevin A McGheeJames J McGoughPatrick J McGrathPeter McGuffinMelvin G McInnisAndrew McIntoshRebecca McKinneyAlan W McLeanFrancis J McMahonWilliam M McMahonAndrew McQuillinHelena MedeirosSarah E MedlandSandra MeierIngrid MelleFan MengJobst MeyerChristel M MiddeldorpLefkos MiddletonVihra MilanovaAna MirandaAnthony P MonacoGrant W MontgomeryJennifer L MoranDaniel Moreno-De-LucaGunnar MorkenDerek W MorrisEric M MorrowValentina MoskvinaPierandrea MugliaThomas W MühleisenWalter J MuirBertram Müller-MyhsokMichael MurthaRichard M MyersInez Myin-GermeysMichael C NealeStan F NelsonCaroline M NievergeltIvan NikolovVishwajit NimgaonkarWillem A NolenMarkus M NöthenJohn I NurnbergerEvaristus A NwuliaDale R NyholtColm O'DushlaineRobert D OadesAnn OlincyGuiomar OliveiraLine OlsenRoel A OphoffUrban OsbyMichael J OwenAarno PalotieJeremy R ParrAndrew D PatersonCarlos N PatoMichele T PatoBrenda W PenninxMichele L PergadiaMargaret A Pericak-VanceBenjamin S PickardJonathan PimmJoseph PivenDanielle PosthumaJames B PotashFritz PoustkaPeter ProppingVinay PuriDigby J QuestedEmma M QuinnJosep Antoni Ramos-QuirogaHenrik B RasmussenSoumya RaychaudhuriKarola RehnströmAndreas ReifMarta RibasésJohn P RiceMarcella RietschelKathryn RoederHerbert RoeyersLizzy RossinAribert RothenbergerGuy RouleauDouglas RuderferDan RujescuAlan R SandersStephan J SandersSusan L SantangeloJoseph A SergeantRussell SchacharMartin SchallingAlan F SchatzbergWilliam A ScheftnerGerard D SchellenbergStephen W SchererNicholas J SchorkThomas G SchulzeJohannes SchumacherMarkus SchwarzEdward ScolnickLaura J ScottJianxin ShiPaul D ShillingStanley I ShynJeremy M SilvermanSusan L SlagerSusan L SmalleyJohannes H SmitErin N SmithEdmund J S Sonuga-BarkeDavid St ClairMatthew StateMichael SteffensHans-Christoph SteinhausenJohn S StraussJana StrohmaierT Scott StroupJames S SutcliffePeter SzatmariSzabocls SzelingerSrinivasa ThirumalaiRobert C ThompsonAlexandre A TodorovFederica TozziJens TreutleinManfred UhrEdwin J C G van den OordGerard Van GrootheestJim Van OsAstrid M VicenteVeronica J VielandJohn B VincentPeter M VisscherChristopher A WalshThomas H WassinkStanley J WatsonMyrna M WeissmanThomas WergeThomas F WienkerEllen M WijsmanGonneke WillemsenNigel WilliamsA Jeremy WillseyStephanie H WittWei XuAllan H YoungTimothy W YuStanley ZammitPeter P ZandiPeng ZhangFrans G ZitmanSebastian ZöllnerBernie DevlinJohn R KelsoePamela SklarMark J DalyMichael C O'DonovanNicholas CraddockPatrick F SullivanJordan W SmollerKenneth S KendlerNaomi R WrayInternational Inflammatory Bowel Disease Genetics Consortium (IIBDGC)
Collaborators

Genetic Relationship Between Five Psychiatric Disorders Estimated From Genome-Wide SNPs

Cross-Disorder Group of the Psychiatric Genomics Consortium et al. Nat Genet.

Abstract

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Figures

Figure 1
Figure 1
Evidence for genome-wide pleiotropy between psychiatric disorders. Proportion of variance in liability (SNP-based heritability) and proportion of covariance in liability between disorder (SNP-based coheritability) for five major psychiatric disorders. The 95% error bars represent the estimates ± 1.96 s.e. SCZ, schizophrenia; MDD, major depressive disorder; BPD, bipolar disorder.
Figure 2
Figure 2
Genomic partitioning of SNP-based heritability and SNP-based coheritability by annotation. Shown is the proportion of SNPs attributable to genes in the CNS+ set (red), the proportion of SNP-based heritability attributable to SNPs in the CNS+ set (dark green), the proportion of SNP-based coheritability attributable to SNPs in the CNS+ set (light green) and the proportion of SNP-based heritability for Crohn’s disease attributed to SNPs in the CNS+ set (orange). The 95% error bars represent the estimates ± 1.96 s.e. ***P < 1 × 10−5 in a test of whether the proportion of heritability explained by SNPs was equal to the proportion of SNP for the CNS+ set.
Figure 3
Figure 3
SNP-based heritabilities and coheritabilities. (a) For each disorder, SNP-based heritabilities are estimated from univariate analyses of the full data set (dark green) or of sample subsets (red and pink bars). These heritabilities are also estimated from bivariate analyses in which different subsets of the same disorder comprise the two traits (blue). Test of the heterogeneity of estimates, P value for Cochran’s Q: schizophrenia, 0.3; bipolar disorder, 1 × 10−6; major depressive disorder, 4 × 10−3; ADHD, 9 × 10−6; ASD, 0.99; Higgins’ I2: schizophrenia, 21%; bipolar disorder, 86%; major depressive disorder, 71%; ADHD, 91%; ASD, 0%). (b) For comparison, the coheritabilities using the full data sets reported in Figure 1 are shown. (c) As a negative control, estimates of coheritabilities with Crohn’s disease, a disease not expected to be genetically related to psychiatric disorders, are shown. We estimated 95% error bars using ± 1.96 s.e.

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