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

Hanna M. Ollila; Eilon Sharon; Ling Lin; Nasa Sinnott-Armstrong; Aditya Ambati; Selina M. Yogeshwar; Ryan P. Hillary; Otto Jolanki; Juliette Faraco; Mali Einen; Guo Luo; Jing Zhang; Fang Han; Han Yan; Xiao Song Dong; Jing Li; Jun Zhang; Seung Chul Hong; Tae Won Kim; Yves Dauvilliers; Lucie Barateau; Gert Jan Lammers; Rolf Fronczek; Geert Mayer; Joan Santamaria; Isabelle Arnulf; Stine Knudsen-Heier; May Kristin Lyamouri Bredahl; Per Medbøe Thorsby; Giuseppe Plazzi; Fabio Pizza; Monica Moresco; Catherine Crowe; Stephen K. Van den Eeden; Michel Lecendreux; Patrice Bourgin; Takashi Kanbayashi; Francisco J. Martínez-Orozco; Rosa Peraita-Adrados; Antonio Benetó; Jacques Montplaisir; Alex Desautels; Yu Shu Huang; FinnGen

doi:10.1038/s41467-023-36120-z

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

Hanna M. Ollila, Eilon Sharon, Ling Lin, Nasa Sinnott-Armstrong, Aditya Ambati, Selina M. Yogeshwar, Ryan P. Hillary, Otto Jolanki, Juliette Faraco, Mali Einen, Guo Luo, Jing Zhang, Fang Han, Han Yan, Xiao Song Dong, Jing Li, Jun Zhang, Seung Chul Hong, Tae Won Kim, Yves DauvilliersLucie Barateau, Gert Jan Lammers, Rolf Fronczek, Geert Mayer, Joan Santamaria, Isabelle Arnulf, Stine Knudsen-Heier, May Kristin Lyamouri Bredahl, Per Medbøe Thorsby, Giuseppe Plazzi, Fabio Pizza, Monica Moresco, Catherine Crowe, Stephen K. Van den Eeden, Michel Lecendreux, Patrice Bourgin, Takashi Kanbayashi, Francisco J. Martínez-Orozco, Rosa Peraita-Adrados, Antonio Benetó, Jacques Montplaisir, Alex Desautels, Yu Shu Huang, FinnGen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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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®.

Original language	English
Article number	2709
Journal	Nature Communications
Volume	14
Issue	1
Number of pages	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-023-36120-z
Publication status	Published - Dec 2023
Externally published	Yes

Keywords

Autoimmune Diseases/epidemiology
Autoimmunity/genetics
Humans
Influenza A Virus, H1N1 Subtype/genetics
Influenza Vaccines/adverse effects
Influenza, Human/epidemiology
Narcolepsy/chemically induced

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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., Zhang, J., Hong, S. C., Kim, T. W., ... FinnGen (2023). Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy. Nature Communications, 14(1), Article 2709. https://doi.org/10.1038/s41467-023-36120-z

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title = "Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy",

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{\textregistered}. 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{\textregistered}.",

keywords = "Autoimmune Diseases/epidemiology, Autoimmunity/genetics, Humans, Influenza A Virus, H1N1 Subtype/genetics, Influenza Vaccines/adverse effects, Influenza, Human/epidemiology, Narcolepsy/chemically induced",

author = "Ollila, {Hanna M.} and Eilon Sharon and Ling Lin and Nasa Sinnott-Armstrong and Aditya Ambati and Yogeshwar, {Selina M.} and Hillary, {Ryan P.} and Otto Jolanki and Juliette Faraco and Mali Einen and Guo Luo and Jing Zhang and Fang Han and Han Yan and Dong, {Xiao Song} and Jing Li and Jun Zhang and Hong, {Seung Chul} and Kim, {Tae Won} and Yves Dauvilliers and Lucie Barateau and Lammers, {Gert Jan} and Rolf Fronczek and Geert Mayer and Joan Santamaria and Isabelle Arnulf and Stine Knudsen-Heier and Bredahl, {May Kristin Lyamouri} and Thorsby, {Per Medb{\o}e} and Giuseppe Plazzi and Fabio Pizza and Monica Moresco and Catherine Crowe and {Van den Eeden}, {Stephen K.} and Michel Lecendreux and Patrice Bourgin and Takashi Kanbayashi and Mart{\'i}nez-Orozco, {Francisco J.} and Rosa Peraita-Adrados and Antonio Benet{\'o} and Jacques Montplaisir and Alex Desautels and Huang, {Yu Shu} and Hao Chen and FinnGen",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-36120-z",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Ollila, HM, Sharon, E, Lin, L, Sinnott-Armstrong, N, Ambati, A, Yogeshwar, SM, Hillary, RP, Jolanki, O, Faraco, J, Einen, M, Luo, G, Zhang, J, Han, F, Yan, H, Dong, XS, Li, J, Zhang, J, Hong, SC, Kim, TW, Dauvilliers, Y, Barateau, L, Lammers, GJ, Fronczek, R, Mayer, G, Santamaria, J, Arnulf, I, Knudsen-Heier, S, Bredahl, MKL, Thorsby, PM, Plazzi, G, Pizza, F, Moresco, M, Crowe, C, Van den Eeden, SK, Lecendreux, M, Bourgin, P, Kanbayashi, T, Martínez-Orozco, FJ, Peraita-Adrados, R, Benetó, A, Montplaisir, J, Desautels, A, Huang, YS & FinnGen 2023, 'Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy', Nature Communications, vol. 14, no. 1, 2709. https://doi.org/10.1038/s41467-023-36120-z

TY - JOUR

T1 - Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

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 - Chen, Hao

AU - FinnGen

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®.

KW - Autoimmune Diseases/epidemiology

KW - Autoimmunity/genetics

KW - Humans

KW - Influenza A Virus, H1N1 Subtype/genetics

KW - Influenza Vaccines/adverse effects

KW - Influenza, Human/epidemiology

KW - Narcolepsy/chemically induced

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 - Journal article

C2 - 37188663

AN - SCOPUS:85159459680

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2709

ER -

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

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