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

FinnGen

doi:10.1038/s41467-023-36120-z

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

FinnGen

Department of Psychiatry

Stanford University
University of Helsinki
Massachusetts General Hospital
Charité – Universitätsmedizin Berlin
Peking University
The Catholic University of Korea, St. Vincent's Hospital
Institut national de la santé et de la recherche médicale
Leiden University
Epilepsy Institutes of the Netherlands Foundation
Hephata Klinik
University of Marburg
University of Barcelona
Assistance publique – Hôpitaux de Paris
University of Oslo
University of Bologna
IRCCS Istituto delle Scienze Neurologiche di Bologna
Mater Private Hospital Dublin
Kaiser Permanente
Université de Paris
Department of Sleep Medicine, Strasbourg University Hospital, Strasbourg University
Akita University
University of Tsukuba
Hospital Clínico San Carlos de Madrid
Hospital General Universitario Gregorio Marañon
Sleep Unit. Medical Center Valencia
University of Montreal
Chang Gung Memorial Hospital
Aarhus University
AbbVie

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

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 number	1
DOIs	https://doi.org/10.1038/s41467-023-36120-z
State	Published - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Cite this

@article{b8902a02965843afbd25ba52abd475f5,

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}.",

author = "FinnGen and 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 Als, \{Thomas Damm\} and Adam Ziemann and Ali Abbasi and Anne Lehtonen and Apinya Lertratanakul and Bridget Riley-Gillis and Fedik Rahimov",

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",

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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

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 - https://www.scopus.com/pages/publications/85159459680

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 -

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

Abstract

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