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Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy. Nature communications 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., Zhang, 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., 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., 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. 2023; 14 (1): 2709

Abstract

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®.

View details for DOI 10.1038/s41467-023-36120-z

View details for PubMedID 37188663

View details for PubMedCentralID PMC10185546