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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 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 Santamaría, Isabelle Arnulf, Stine Knudsen, 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, F Martínez-Orozco, Rosa Peraita‐Adrados, Antonio Benetó, Jacques Montplaisir, Alex Désautels, Yu‐Shu Huang, Thomas D. Als, Adam Ziemann, Ali Abbasi, Anne Lehtonen, Apinya Lertratanakul, Bridget Riley‐Gillis, Fedik Rahimov, Howard J. Jacob, Jeffrey F. Waring, Mengzhen Liu, Nizar Smaoui, Relja Popovic, Adam Platt, Athena Matakidou, Benjamin Challis, Dirk S. Paul, Glenda Lassi, Ioanna Tachmazidou, Antti Hakanen, Johanna Schleutker, Nina Pitkänen, Perttu Terho, Petri Virolainen, Arto Mannermaa, Veli‐Matti Kosma, Chia‐Yen Chen, Heiko Runz, Sally John, Sanni Lahdenperä, Stephanie Loomis, Susan Eaton, George Okafo, Heli Salminen‐Mankonen, Marc Jung, Nathan Lawless, Zhihao Ding, Joseph Maranville, Marla Hochfeld, Robert M. Plenge, Shameek Biswas, Masahiro Kanai, Mutaamba Maasha, Wei Zhou, Outi Tuovila, Raimo Pakkanen, Jari A. Laukkanen, Teijo Kuopio, Kristiina Aittomäki, Antti Mäkitie, Natalia Pujol, Triin Laisk, Katriina Aalto‐Setälä, Johanna Mäkelä, Marco Hautalahti, Sarah Smith, Tom Southerington, Eeva Kangasniemi, Henna Palin, Mika Kähönen, Sanna Siltanen, Tarja Laitinen, Felix Vaura, Jaana Suvisaari, Teemu Niiranen, Veikko Salomaa, Jukka Partanen, Mikko Arvas, Jarmo Ritari, Kati Hyvärinen, David F. Choy, Edmond Teng, Erich C. Strauss, Hao Chen, Hubert Chen, Jennifer L. Schutzman, Julie Hunkapiller, Mark I. McCarthy, Natalie Bowers, Rion Pendergrass, Tim Lu, Audrey Y. Chu, Diptee Kulkarni, Fanli Xu, Joanna Betts, John D. Eicher, Jorge Esparza Gordillo, Laura Addis, Linda McCarthy, Rajashree Mishra, Janet Kumar, Margaret G. Ehm, Kirsi Auro, David Pulford, Anne Pitkäranta, Anu Loukola, Eero Punkka, Malla-Maria Linna, Olli Carpén, Taneli Raivio, Joni A. Turunen, Tomi P. Mäkelä, Aino Salminen, Antti A. Aarnisalo, Daniel Gordin, David Rice, Erkki Isometsä, Eveliina Salminen, Heikki Joensuu, Ilkka Kalliala, Johanna Mattson, Juha Sinisalo, Jukka Koskela, Kari K. Eklund, Katariina Hannula‐Jouppi, Lauri A. Aaltonen, Marja‐Riitta Taskinen, Martti Färkkilâ, Minna Raivio, Oskari Heikinheimo, Pekka Nieminen, Pentti Tienari, Pirkko J. Pussinen, Sampsa Pikkarainen, Terhi Ollila, Timo P. Hiltunen, Tuomo J Meretoja, Tuula Salo, Ulla Palotie, Antti Palomäki, Jenni Aittokallio, Juha O. Rinne, Kaj Metsärinne, Klaus Elenius, Laura Pirilä, Leena Koulu, Markku Voutilainen, Riitta Lahesmaa, Roosa Kallionpää, Sirkku Peltonen, Tytti Willberg, Ulvi Kahraman Gürsoy, Varpu Jokimaa, Aarno Palotie, Anastasia Kytölä, Andrea Ganna, Anu Jalanko, Aoxing Liu, Arto Lehistö, Awaisa Ghazal, Elina Kilpeläinen, Elisabeth Widén, Elmo Saarentaus, Esa Pitkänen, Hannele Laivuori, Henrike Heyne, Huei-Yi Shen, Jaakko Kaprio, Joel Rämö, Juha Karjalainen, Juha Mehtonen, Jyrki Pitkänen, Kalle Pärn, Kati Donner, Katja Kivinen, L. Elisa Lahtela, Mari Niemi, Mari Kaunisto, Mart Kals, Mary Pat Reeve, Mervi Aavikko, Nina Mars, Oluwaseun Alexander Dada, Pietro Della Briotta Parolo, Priit Palta, Rigbe Weldatsadik, Risto Kajanne, Rodos Rodosthenous, Samuli Ripatti, Sanni Ruotsalainen, Satu Strausz, Shabbeer Hassan, Shanmukha Sampath Padmanabhuni, Shuang Luo, Susanna Lemmelä, Taru Tukiainen, Timo P. Sipilä, Tuomo Kiiskinen, Vincent Llorens, Mark J. Daly, Jiwoo Lee, Kristin Tsuo, Mitja Kurki, Amanda Elliott, Aki S. Havulinna, Juulia Partanen, Robert Yang, Dermot F. Reilly, Alessandro Porello, Amy Hart, Dawn Waterworth, Ekaterina Khramtsova, Karen He, Meijian Guan, Qingqin S. Li, Sauli Vuoti, Eric Green, Robert Graham, Sahar V. Mozaffari, Adriana Huertas‐Vázquez, Andrey Loboda, Caroline S. Fox, Fabiana Farias, Jae-Hoon Sul, Jason Miller, Neha Raghavan, Simonne Longerich, Johannes Kettunen, Raisa Serpi, Reetta Hinttala, Tuomo Mantere, Anne M. Remes, Elisa Rahikkala, Johanna Huhtakangas, Kaisa Tasanen, Laura Huilaja, Laure Morin‐Papunen, Maarit Niinimäki, Marja Vääräsmäki, Outi Uimari, Peeter Karihtala, Terhi Piltonen, Terttu Harju, Timo Blomster, Vuokko Anttonen, Hilkka Soininen, Kai Kaarniranta, Liisa Suominen, Margit Pelkonen, Maria Siponen, Mikko Kiviniemi, Oili Kaipiainen‐Seppänen, Päivi Auvinen, Päivi Mäntylä, Reetta Kälviäinen, Valtteri Julkunen, Chris O’Donnell, Ma ́en Obeidat, Nicole Renaud, Debby Ngo, Majd Mouded, Mike Mendelson, Anders Mälarstig, Heli Lehtonen, Jaakko Parkkinen, Kirsi Kalpala, Melissa Miller, Nan Bing, Stefan McDonough, Xinli Hu, Ying Wu, Airi Jussila, Annika Auranen, Argyro Bizaki-Vallaskangas, Hannu Uusitalo, Jukka Peltola, Jussi Hernesniemi, Katri Kaukinen, Laura Kotaniemi‐Talonen, Pia Isomäki, Teea Salmi, Venla Kurra, Kirsi Sipilä, Auli Toivola, Elina Järvensivu, Essi Kaiharju, Hannele Mattsson, Kati Kristiansson, Lotta Männikkö, Markku Laukkanen, Markus Perola, Minna Brunfeldt, Päivi Laiho, Regis Wong, Sami Koskelainen, Sini Lähteenmäki, Sirpa Soini, Teemu Paajanen, Terhi Kilpi, Tero Hiekkalinna, Tuuli Sistonen, Clément Chatelain, Deepak Raipal, K. Klinger, Samuel Lessard, Fredrik Åberg, Mikko Hiltunen, Sami Heikkinen, Hannu Kankaanranta, Tuula Palotie, Iiris Hovatta, Kimmo Palin, Niko Välimäki, Sanna Toppila‐Salmi, Eija K. Laakkonen, Eeva Sliz, Heidi Silven, Katri Pylkäs, Minna K. Karjalainen, Riikka K. Arffman, Susanna Savukoski, Jaakko Tyrmi, Harri Siirtola, Iida Vähätalo, Javier Gracia‐Tabuenca, Marianna Niemi, Mika Helminen, Tiina Luukkaala, Poul Jennum, Soňa Nevšímalová, David Kemlink, Álex Iranzo, Sebastiaan Overeem, Aleksandra Wierzbicka, Peter Geisler, Karel Šonka, Makoto Honda, Birgit Högl, Ambra Stefani, Fernando Morgadinho Santos Coelho, Vilma Mantovani, Eva Feketeová, Mia Wadelius, Niclas Eriksson, Hans Smedje, Pär Hallberg, Per Egil Hesla, David B. Rye, Zerrin Pelin, Luigi Ferini‐Strambi, Claudio L. Bassetti, Johannes Mathis, Ramin Khatami, Adi Aran, Sheela Nampoothiri, Tomas Olsson, Ingrid Kockum, Markku Partinen, Birgitte Rahbek Kornum, Sina Rüeger, Juliane Winkelmann, Taku Miyagawa, Hiromi Toyoda, Seik‐Soon Khor, Mihoko Shimada, Katsushi Tokunaga, Jonathan K. Pritchard, Neil Risch, Zoltán Kutalik, Ruth O’Hara, Joachim Hallmayer, Chun Ye, Emmanuel Mignot
Bibliographic record
VenueNature Communications · 2023
Typearticle
Languageen
FieldNeuroscience
TopicSleep and Wakefulness Research
Canadian institutionsCanadian Sleep & Circadian NetworkUniversité de MontréalHôpital du Sacré-Cœur de Montréal
FundersJanssen BiotechNational Institute of Neurological Disorders and StrokeNational Institute of Allergy and Infectious DiseasesNational Institute of Mental HealthKey ProgrammeNational Defense Science and Engineering GraduateInstrumentariumin TiedesäätiöSigrid Juséliuksen SäätiöSuomen KulttuurirahastoAcademy of FinlandGenentechNational Natural Science Foundation of ChinaBusiness FinlandU.S. Department of Health and Human ServicesDeutscher Akademischer AustauschdienstMaze TherapeuticsYrjö Jahnssonin SäätiöJazz PharmaceuticalsEtelä-Karjalan RahastoJalmari ja Rauha Ahokkaan SäätiöPfizerBiogenNovartisCelgeneStanford Research Computing Center, Stanford UniversityAbbVieU.S. Department of DefenseSanofiBristol-Myers SquibbNational Institutes of HealthGlaxoSmithKline
KeywordsNarcolepsyImmunologyBiologyAutoimmunityGenome-wide association studyImmune systemHuman leukocyte antigenGeneticsSingle-nucleotide polymorphismGenotypeGeneAntigen
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®.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.002
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: none
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.264
Threshold uncertainty score0.838
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.028
GPT teacher head0.326
Teacher spread0.298 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designBench or experimental
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations61
Published2023
Admission routes1
Has abstractyes