biostudies-literatureOllila HMInstrumentariumin TiedesäätiöGlaxoSmithKlineU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesSigrid Juséliuksen SäätiöNIAID NIH HHSNIMH NIH HHSFinnish Cultural Foundation | Etelä-Karjalan RahastoNational Science Foundation of China | Key ProgrammeAcademy of FinlandU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeCharité Universitat medizin Berlin, PhD fellowshipNINDS NIH HHSJazz Pharmaceuticals2709https://www.ebi.ac.uk/biostudies/studies/S-EPMC10185546biostudies-literatureUnknown14(1)Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by Nature communicationsNarcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.PMC10185546R01 AI144798NS23723P50 NS023724NS23724AI144798RC2 MH0899168142010800230964381670087Khatami RHelminen MHarju TObeidat MEArvas MSoini SAddis LBowers NAbbasi ANgo DMakela TPMeretoja TMathis JXu FAberg FCrowe CPlatt AFronczek RSuominen LDong XSSoininen HTuomi TMiller MJennum PMiller JHogl BHillary RPSavukoski SRipatti SUimari OBredahl MKLKytola AHuertas-Vazquez AReilly DKim TWPiltonen TMignot EJMishra RFarias FWong RHeikinheimo OHallmayer JBeneto ALinna MMHochfeld MKristiansson KWillberg TElenius KLoukola APerola MReeve MPPizza FRemes AWaring JKoskelainen SRaghavan NHassan SLongerich SAarnisalo APalin KParkkinen JPalin HWeldatsadik RBetts JJacob HPaul DKulkarni DPelkonen MBizaki-Vallaskangas ADauvilliers YTerho PRaipal DNiemi MSmedje HKahonen MKanbayashi TChen HTienari PPritchard JKKuopio TAuvinen PTeng EKaarniranta KEriksson NPlenge RLiu MChallis BPylkas KSliz EYe CJKlinger KSchutzman JAnttonen VGhazal AStrauss ERueger SSipila TPSaarentaus EAuro KGuan MPorello ALiu ASantamaria JSinisalo JMannermaa AJulkunen VKangasniemi EPunkka EFarkkila MLemmela SDaly MLahesmaa RWadelius MShimada MSistonen TMars NLaivuori HKnudsen-Heier SAls TDNampoothiri SVaura FFox COllila HMKalpala KRisch NMakela JPartanen JLertratanakul ALaiho PHong SCLaukkanen MLaukkanen JOkafo GJussila APakkanen RRunz HDesautels ABrunfeldt MSerpi RKhor SSMaranville JJokimaa VMcDonough SLahtela LENiemi MEKaunisto MJalanko AVaarasmaki MRamo JJolanki OPeltonen SHautalahti MRenaud NTukiainen TAavikko MHan FAran AIsometsa ESuvisaari JDada OAKankaanranta HVuoti SPikkarainen SRahimov FNiiranen TAittomaki KElliott AKemlink DPadmanabhuni SSRitari JGordillo JEToyoda HTaskinen MRVoutilainen MHiltunen TRiley-Gillis BAittokallio JCoelho FMHiltunen MEicher JKiiskinen TWierzbicka AKauppi PWinkelmann JKutalik ZKaukinen KAuranen AMayer GLehtonen ABassetti CLChoy DLehisto ARahikkala EMorin-Papunen LLehtonen HWaterworth DSalmi TKaipiainen-Seppanen OKiviniemi MKoulu LArnulf ISmith SPalta PKallionpaa RPussinen PYan HNevsimalova SMattsson HGarcia-Tabuenca JGeisler PLahteenmaki SBiswas SKaprio JHu XHunkapiller JPendergrass RSmaoui NJohn SBlomster TFinnGenVahatalo IToivola AHart ABing NLaitinen TRodosthenous RZiemann AKalliala IHe KJoensuu HLawless NHallberg PSiirtola HTachmazidou IFaraco JSonka KLin LMehtonen JOllila TKarihtala PSipila KOvereem SSalminen ETurunen JAGursoy UDonner KWiden ESchleutker JHiekkalinna TKettunen JFeketeova EGreen EGanna ASalminen AToppila-Salmi SOllila HHonda MSilven HKotaniemi-Talonen LKockum IPopovic RJarvensivu ETuovila OTsuo KMantyla PKilpelainen EPaajanen TOlsson TChen CYPujol NBourgin PKoskela JLi JHakanen AHavulinna AMoresco MRaivio TSul JHSiltanen STasanen KStrausz SRinne JRaivio MEinen MValimaki NLoboda AVirolainen PRivas MTyrmi JMaasha MMannikko LUusitalo HEhm MGMantere TPalomaki AHuang YSThorsby PMDella Briotta Parolo PHovatta ILuo GParn KHeyne HLessard SLuukkaala THinttala RO'Donnell CLuo SKivinen KMendelson MMatakidou AZhang JO'Hara RPulford DPalotie ALassi GMantovani VSinnott-Armstrong NHuilaja LLaakkonen EAalto-Setala KSharon EMcCarthy MPalotie UPalotie TMcCarthy LHernesniemi JAaltonen LMiyagawa TKanai MMakitie AMattson JRye DRice DPirila LIsomaki PArffman RPeraita-Adrados RSalomaa VLee JShen HYSalo TChu ALoomis SKurra VKilpi TMartinez-Orozco FJHuhtakangas JLammers GJTokunaga KKhramtsova EKarjalainen MKarjalainen JPitkaranta AZhou WEklund KMalarstig AYogeshwar SMChatelain CJung MNieminen PMontplaisir JPitkanen EKosma VMSalminen-Mankonen HFerini-Strambi LPeltola JNiinimaki MBarateau LSoutherington TLlorens VKornum BRAmbati AMetsarinne KPitkanen JPlazzi GWu YPitkanen NEaton SKurki MMozaffari SHeikkinen SGraham RMouded MLu THannula-Jouppi KYang RGordin DVan den Eeden SKSiponen MIranzo ALahdenpera SHesla PEHyvarinen KCarpen OLi QSDing ZLaisk TKaiharju EKalviainen RLecendreux MPartinen MRuotsalainen SKals MKajanne RKumar JPelin ZStefani AfalseNarcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by 2023-01-01T00:00:00Z2023 May2026-05-29T19:20:16.044Z2024-12-03T21:38:59.663ZS-EPMC101855463718866310.1038/s41467-023-36120-z