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Ollila, H.M.* ; Sharon, E.* ; Lin, L.* ; Sinnott-Armstrong, N.* ; Ambati, A.* ; Yogeshwar, S.M.* ; Hillary, R.P.* ; Jolanki, O.* ; Faraco, J.* ; Einen, M.* ; Luo, G.* ; Zhang, J.* ; Han, F.* ; Yan, H.* ; Dong, X.S.* ; Li, J.* ; Hong, S.C.* ; Kim, T.W.* ; Dauvilliers, Y.* ; Barateau, L.* ; Lammers, G.J.* ; Fronczek, R.* ; Mayer, G.* ; Santamaría, J.* ; Arnulf, I.* ; Knudsen-Heier, S.* ; Bredahl, M.K.L.* ; Thorsby, P.M.* ; Plazzi, G.* ; Pizza, F.* ; Moresco, M.* ; Crowe, C.* ; Van den Eeden, S.K.* ; Lecendreux, M.* ; Bourgin, P.* ; Kanbayashi, T.* ; Martínez-Orozco, F.J.* ; Peraita-Adrados, R.* ; Benetó, A.* ; Montplaisir, J.* ; Desautels, A.* ; Huang, Y.S.* ; Jennum, P.* ; Nevsimalova, S.* ; Kemlink, D.* ; Iranzo, A.* ; Overeem, S.* ; Wierzbicka, A.* ; Geisler, P.* ; Sonka, K.* ; Honda, M.* ; Högl, B.* ; Stefani, A.* ; Coelho, F.M.* ; Mantovani, V.* ; Feketeova, E.* ; Wadelius, M.* ; Eriksson, N.* ; Smedje, H.* ; Hallberg, P.* ; Hesla, P.E.* ; Rye, D.* ; Pelin, Z.* ; Ferini-Strambi, L.* ; Bassetti, C.L.* ; Mathis, J.* ; Khatami, R.* ; Aran, A.* ; Nampoothiri, S.* ; Olsson, T.* ; Kockum, I.* ; Partinen, M.* ; Perola, M.* ; Kornum, B.R.* ; Rüeger, S.* ; Winkelmann, J. ; Miyagawa, T.* ; Toyoda, H.* ; Khor, S.S.* ; Shimada, M.* ; Tokunaga, K.* ; Rivas, M.* ; Pritchard, J.K.* ; Risch, N.* ; Kutalik, Z.* ; O'Hara, R.* ; Hallmayer, J.* ; Ye, C.J.* ; Mignot, E.J.*

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.

Nat. Commun. 14:2709 (2023)

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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®.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Genome-wide Association; Hla-dq; Genotype Imputation; Confer Risk; Expression; Reconstruction; Transcriptome; Epidemiology; Vaccination; Protection

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 14, Issue: 1, Article Number: 2709

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants German-Academic Exchange Service (DAAD)
Einstein Center for Neurosciences
NSFC
Ministry of Science and Technology
Swedish medical product agency
Jazz Pharmaceuticals
National Institute of Mental Health
GlaxoSmithKline
Stanford University through the Stanford Graduate Fellowship program
United States Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) program
Jalmari and Rauha Ahokas Foundation
Instrumentarium Science Foundation
Orion Farmos Research Foundation
Finnish Cultural Foundation
Sigrid Juselius Foundation
Academy of Finland
wake-up narcolepsy
Academy of Finland (AKA)

BBMRI-ERIC operations in Finland
Finnish Biobank Cooperative-FINBB
Finnish Clinical Biobank Tampere
Biobank Borealis of Northern Finland
THL Biobank
NIMH
Novartis AG
Sanofi US Services Inc.
GlaxoSmithKline Intellectual Property Development Ltd.
Merck Sharp Dohme Corp.
Genentech Inc.
Biogen MA Inc.
Stanford University - Business Finland
Boehringer Ingelheim