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Ollila, H.M.; Sharon, E.; Lin, L.; Sinnott-Armstrong, N.; Ambati, A.; Yogeshwar, S.M.; ... ; Mignot, E.J. (2023)

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

Article / Letter to editor
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...Show more 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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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.; Santamaria, J.; Arnulf, I.; Knudsen-Heier, S.; Bredahl, M.K.L.; Thorsby, P.M.; Plazzi, G.; Pizza, F.; Moresco, M.; Crowe, C.; Eeden, S.K. van den; Lecendreux, M.; Bourgin, P.; Kanbayashi, T.; Martinez-Orozco, F.J.; Peraita-Adrados, R.; Benetó, A.; Montplaisir, J.; Desautels, A.; Huang, Y.S.; FinnGen, P.J.; 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.; Rueger, 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.
Date
2023-05-15
Journal
Nature Communications
Volume
14
Issue
1
DOI
doi:10.1038/s41467-023-36120-z
Link
https://www.nature.com/articles/s41467-023-36120-z