TY - JOUR
T1 - Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
AU - FinnGen
AU - Ollila, Hanna M.
AU - Sharon, Eilon
AU - Lin, Ling
AU - Sinnott-Armstrong, Nasa
AU - Ambati, Aditya
AU - Yogeshwar, Selina M.
AU - Hillary, Ryan P.
AU - Jolanki, Otto
AU - Faraco, Juliette
AU - Einen, Mali
AU - Luo, Guo
AU - Zhang, Jing
AU - Han, Fang
AU - Yan, Han
AU - Dong, Xiao Song
AU - Li, Jing
AU - Zhang, Jun
AU - Hong, Seung Chul
AU - Kim, Tae Won
AU - Dauvilliers, Yves
AU - Barateau, Lucie
AU - Lammers, Gert Jan
AU - Fronczek, Rolf
AU - Mayer, Geert
AU - Santamaria, Joan
AU - Arnulf, Isabelle
AU - Knudsen-Heier, Stine
AU - Bredahl, May Kristin Lyamouri
AU - Thorsby, Per Medbøe
AU - Plazzi, Giuseppe
AU - Pizza, Fabio
AU - Moresco, Monica
AU - Crowe, Catherine
AU - Van den Eeden, Stephen K.
AU - Lecendreux, Michel
AU - Bourgin, Patrice
AU - Kanbayashi, Takashi
AU - Martínez-Orozco, Francisco J.
AU - Peraita-Adrados, Rosa
AU - Benetó, Antonio
AU - Montplaisir, Jacques
AU - Desautels, Alex
AU - Huang, Yu Shu
AU - Als, Thomas Damm
AU - Ziemann, Adam
AU - Abbasi, Ali
AU - Lehtonen, Anne
AU - Lertratanakul, Apinya
AU - Riley-Gillis, Bridget
AU - Rahimov, Fedik
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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®.
AB - 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®.
UR - http://www.scopus.com/inward/record.url?scp=85159459680&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-36120-z
DO - 10.1038/s41467-023-36120-z
M3 - Article
C2 - 37188663
AN - SCOPUS:85159459680
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2709
ER -
