Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.
Hanna M OllilaEilon SharonLing LinNicholas A Sinnott-ArmstrongAditya AmbatiSelina M YogeshwarRyan P HillaryOtto JolankiJuliette FaracoMali EinenGuo LuoJing ZhangFang HanHan YanXiao Song DongJing LiJun ZhangSeung-Chul HongTae Won KimYves DauvilliersLucie BarateauGert Jan LammersRolf FronczekGeert MayerJoan SantamariaIsabelle ArnulfStine Knudsen-HeierMay Kristin Lyamouri BredahlPer Medbøe ThorsbyGiuseppe PlazziFabio PizzaMonica MorescoCatherine CroweStephen K Van den EedenMichel LecendreuxPatrice BourginTakashi KanbayashiFrancisco J Martínez-OrozcoRosa Peraita-AdradosAntonio BenetóJacques MontplaisirAlex DesautelsYu-Shu Huangnull nullPoul JennumSona NevsimalovaDavid KemlinkAlex IranzoSebastiaan OvereemAleksandra WierzbickaPeter GeislerKarel SonkaMakoto HondaBirgit HöglAmbra StefaniFernando Morgadinho CoelhoVilma MantovaniLukrécia MertováMia WadeliusNiclas ErikssonHans SmedjePär HallbergPer Egil HeslaDavid RyeZerrin PelinLuigi Ferini-StrambiClaudio L BassettiJohannes MathisRamin KhatamiAdi AranSheela NampoothiriTomas OlssonIngrid KockumMarkku PartinenMarkus PerolaBirgitte Rahbek KornumSina RuegerJuliane WinkelmannTaku MiyagawaHiromi ToyodaSeik-Soon KhorMihoko ShimadaKatsushi TokunagaManuel A RivasJonathan K PritchardNeil RischZoltán KutalikRuth O'HaraJoachim HallmayerChun Jimmie YeEmmanuel Jean-Marie MignotPublished in: Nature communications (2023)
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 dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.
Keyphrases
- risk factors
- genome wide
- sars cov
- genome wide association study
- coronavirus disease
- genome wide association
- acute lymphoblastic leukemia
- dendritic cells
- human health
- life cycle
- big data
- air pollution
- gene expression
- regulatory t cells
- immune response
- artificial intelligence
- tyrosine kinase
- binding protein
- copy number