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

FinnGen; Sebastiaan Overeem; Emmanuel Mignot

doi:10.1038/s41467-023-36120-z

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

FinnGen
, Sebastiaan Overeem
, Emmanuel Mignot (Corresponding author)

Signal Processing Systems

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

53 Citations (Scopus)

122 Downloads (Pure)

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
Number of pages	13
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36120-z
Publication status	Published - 15 May 2023

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

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

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10.1038/s41467-023-36120-z

pdfFinal published version, 4.29 MBLicence: CC BY

Cite this

@article{bcb4d827c3ad4a97bf25f7d88f1f1c0e,

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

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 Seung-Chul Hong 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 Yu-Shu Huang and Poul Jennum and Sona Nevsimalova and David Kemlink and Alex Iranzo and Sebastiaan Overeem and Aleksandra Wierzbicka and Peter Geisler and Emmanuel Mignot",

year = "2023",

month = may,

day = "15",

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

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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 - Jennum, Poul

AU - Nevsimalova, Sona

AU - Kemlink, David

AU - Iranzo, Alex

AU - Overeem, Sebastiaan

AU - Wierzbicka, Aleksandra

AU - Geisler, Peter

AU - Mignot, Emmanuel

PY - 2023/5/15

Y1 - 2023/5/15

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 - Humans

KW - Autoimmunity/genetics

KW - Influenza, Human/epidemiology

KW - Influenza A Virus, H1N1 Subtype/genetics

KW - Autoimmune Diseases/epidemiology

KW - Influenza Vaccines/adverse effects

KW - Narcolepsy/chemically induced

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

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

UN SDGs

Keywords

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Sleep Medicine

Researchers from Stanford University Discuss Findings in Narcolepsy (Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy)

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

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Research areas

Sleep Medicine

Press/Media

Researchers from Stanford University Discuss Findings in Narcolepsy (Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy)

Cite this