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Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by <i>HLA-DRB1*04</i> subtypes
Yann Le Guen, Guo Luo, Aditya Ambati, Vincent Damotte, Iris E. Jansen, Eric Yu, Aude Nicolas, Thiago Peixoto Leal, Akinori Miyashita, Céline Bellenguez, Michelle Mulan Lian, Kayenat Parveen, Takashi Morizono, Hyeonseul Park, Benjamin Grenier‐Boley, Tatsuhiko Naito, Fahri Küçükali, Seth D. Talyansky, Selina Yogeshwar, Vicente Peris Sempere, Wataru Satake, Victoria Álvarez, Beatrice Arosio, Michaël E. Belloy, Luisa Benussi, Anne Boland, Barbara Borroni, María J. Bullido, Paolo Caffarra, Jordi Clarimón, Antonio Daniele, D.H. Darling, Stéphanie Debette, Jean‐François Deleuze, Martin Dichgans, Carole Dufouil, Emmanuel During, Emrah Düzel, Daniela Galimberti, Guillermo García‐Ribas, José María García‐Alberca, Vilmantas Giedraitis, Oliver Goldhardt, Caroline Graff, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann‐Heimbach, Henne Holstege, Jakub Hort, Yoo Jin Jung, Jürgen Deckert, Silke Kern, Teemu Kuulasmaa, Kun Ho Lee, Ling Lin, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Alexandre de Mendonça, Merçé Boada, Pablo Mir, Susanne Moebus, Fermín Moreno, Benedetta Nacmias, Gaël Nicolas, Shumpei Niida, Børge G. Nordestgaard, Goran Papenberg, Janne M. Papma, Lucilla Parnetti, Florence Pasquier, Pau Pástor, Oliver Peters, Yolande A.L. Pijnenburg, Gerard Piñol‐Ripoll, Julius Popp, Laura Molina‐Porcel, Raquel Puerta, Jordi Pérez‐Tur, Innocenzo Rainero, Inez H.G.B. Ramakers, Luís Miguel Real, Steffi G. Riedel‐Heller, Eloy Rodríguez‐Rodríguez, Owen A. Ross, José Luís Royo, Dan Rujescu, Nikolaos Scarmeas, Philip Scheltens, Norbert Scherbaum, Anja Schneider, Davide Seripa, Ingmar Skoog, Vincenzo Solfrizzi, Gianfranco Spalletta, Alessio Squassina, John C. van Swieten, Raquel Sánchez‐Valle, Eng‐King Tan, Thomas Tegos, Charlotte E. Teunissen, Jesper Qvist Thomassen, Lucio Tremolizzo, Martin Vyhnálek, Frans Verhey, Margda Wærn, Jens Wiltfang, Jing Zhang, Henrik Zetterberg, Kaj Blennow, Zihuai He, Julie Williams, Philippe Amouyel, Frank Jessen, Patrick G. Kehoe, Cornelia van Duin, Magda Tsolaki, Pascual Sánchez‐Juan, Ruth Frikke‐Schmidt, Kristel Sleegers, Tatsushi Toda, Anna Zettergren, Martin Ingelsson, Yukinori Okada, Mikko Hiltunen, Jungsoo Gim, Kouichi Ozaki, Jia Nee Foo, Wiesje M. van der Flier, Takeshi Ikeuchi, Alfredo Ramı́rez, Ignácio F. Mata, Agustı́n Ruiz, Ziv Gan‐Or, Jean‐Charles Lambert, Michael D. Greicius, Emmanuel Mignot, Víctor Andrade, Sonia Moreno–Grau, Najaf Amin, Rafael Campos-Martín, Peter Holmans, Luca Kleineidam, Sven J. van der Lee, Amber Yaqub, Marcos R. Costa, Julien Chapuis, Shahzad Ahmad, Pablo García‐González, Carla Abdelnour, Emilio Alarcón‐Martín, Daniel Alcolea, Montserrat Alegret, Ignacio Álvarez, Nicola J. Armstrong, Tsolaki Anthoula, Ildebrando Appollonio, Marina Arcaro, Silvana Archetti, Alfonso Arias Pastor, Henri Bailly, Nerisa Banaj, Miquel Baquero, Ana Belén Pastor, Claudine Berr, Céline Besse, Valentina Bessi, Giuliano Binetti, Alessandra Bizarro, Rafael Blesa, Silvia Boschi, Paola Bossù, Geir Bråthen, Catherine Bresner, Henry Brodaty, Keeley J. Brookes, Luis Ignacio Brusco, Dolores Buiza‐Rueda, Katharina Bürger, Miguel Calero, Geneviève Chêne, Ãngel Carracedo, Roberta Cecchetti, Laura Cervera‐Carles, Camille Charbonnier, Caterina Chillotti, Simona Ciccone, Jurgen A.H.R. Claassen, Christopher Clark, Elisa Conti, Anaïs Corma‐Gómez, Emanuele Maria Costantini, Carlo Custodero, Delphine Daian, Carolina Dalmasso, Efthimios Dardiotis, Jean‐François Dartigues, Peter Paul De Deyn, Teodoro del Ser, Nicola Denning, Janine Diehl‐Schmid, Mónica Díez-Fairén, Paolo Rossi, Srdjan Djurovic, Emmanuelle Duron, Ana Espinosa, Michael Ewers, Marta Fernández‐Fuertes, Catarina B. Ferreira, Evelyn Ferri, Bertrand Fin, Peter Fischer, Tormod Fladby, Klaus Fließbach, Juan Fortea, Silvia Fostinelli, Nick C. Fox, Emlio Franco-Macías, Ana Frank, Lutz Froelich, Sebastián García‐Madrona, Roberta Ghidoni, Giaccone Giorgio, Antonio González-Pérez, Giulia Grande, Emma Green, Timo Grimmer, Tamar Guetta‐Baranes, Annakaisa Haapasalo, Georgios M. Hadjigeorgiou, Harald Hampel, Annette M. Hartmann, Janet Harwood, Seppo Helisalmi, Michael T. Heneka, Martin J. Herrmann, Clive Holmes, Raquel Huerto Vilas, Marc Hulsman, Charlotte Johansson, Lena Kilander, Anne Kinhult Ståhlbom, Miia Kivipelto, Anne M. Koivisto, Johannes Kornhuber, Mary H. Kosmidis, Carmen Lage, Erika J. Laukka, Alessandra Lauria, Jenni Lehtisalo, Ondřej Lerch, Alberto Lleó, Malin Löwemark, Lauren Luckcuck, Juan Macı́as, Catherine Macleod, Wolfgang Maier, Francesca Mangialasche, Spallazzi Marco, Marta Marquié, Iain Marshall, Ángel Martín Montes, Carmen Martínez Rodríguez, Simon Mead, Miguel Medina, Silvia Mendoza, Manuel Menéndez‐González, Merel O. Mol, Laura Montrreal, Laura Morelli, Kevin Morgan, Markus M. Möthen, Carolina Muchnik, Tiia Ngandu, Robert Olaso, Adelina Orellana, Michela Orsini, Gemma Ortega, Alessandro Padovani, Alba Pérez‐Cordón, Pierre Péricard, Juan A. Pineda, Claudia Pisanu, Thomas Polak, Daniëlle Posthuma, Josef Priller, Olivier Quenez, Inés Quintela, Alberto Rábano, Inez Ramakers, Marcel Reinders, Peter Riederer, Natalia Roberto, Irene Rosas Allende, Maitée Rosende‐Roca, Elisa Rubino, María Eugenia Sáez, Paraskevi Sakka, Ingvild Saltvedt, Ángela Sanabria, María Bernal Sánchez‐Arjona, Florentino Sánchez-García, Sigrid Botne Sando, Michela Scamosci, Elio Scarpini, Matthias Schmid, Geir Selbæk, Olivia Anna Skrobot, Hilkka Soininen, Alina Solomon, Sandro Sorbi, Óscar Sotolongo‐Grau, Annika Spottke, Eystein Stordal, Juan Pablo Tartan, Lluís Tárraga, Niccoló Tesi, Anbupalam Thalamuthu, Latchezar Traykov, Anne Tybjærg‐Hansen, André G. Uitterlinden, Abbe Ullgren, Ingun Ulstein, Sergi Valero, Aad van der Lugt, Jasper Van Dongen, Jeroen van Rooij, Rik Vandenberghe, Jean‐Sébastien Vidal, Jonathan Vogelgsang, Michael Wagner, Leonie Weinhold, Gill Windle, Bob Woods, Mary Yannakoulia, Miren Zulaica, Jan Laczó, Václav Maťoška, María Serpente, Francesca Assogna, Fabrizio Piras, Valentina Ciullo, Jacob Shofany, Carlo Ferrarese, Simona Andreoni, Gessica Sala, C Zoia, Maria Del Zompo, Alberto Benussi, Patrizia Bastiani, Mari Takalo, Teemu Natunen, Tiina Laatikainen, Jaakko Tuomilehto, Riitta Antikaínen, Timo Strandberg, Jaana Lindström, Markku Peltonen, Nicholas Bass, Kristelle S. Brown, John Collinge, David W. Craig, Pangiotis Deloukas, Michael Gill, Rhian Gwilliam, John Hardy, Denise Harold, Paul Hollingworth, Jarret A. Johnston, Lesley Jones, Gill Livingston, Simon Lovestone, Michelle K. Lupton, Aoibhinn Lynch, David Mann, Bernadette McGuinness, Michael O‘Donovan, Michael J. Owen, Peter Passmore, John Powell, Christopher E. Shaw, A. David Smith, Hugh Gurling, Catherine J. Mummery, Nathalie Ryan, Giordano Lacidogna, Ad Adarmes-Gómez, Ana Mauleón, Ana Pancho, A. Gailhajenet, Asunción Lafuente, Daniel Macías‐García, Elvira Martín, Esther Pelejà, Isabel Sastre Merlín, L. Garrote-Espina, Liliana Vargas, Mario Carrión‐Claro, María Esmeralda Arreola Marín, Ma Labrador, Mar Buendía, M. D. Alonso, Marina Guitart, Mariona Moreno, Marta Ibarria, Mt Periñán, Núria Aguilera, Pilar Cañabate, R. Pineda-Sanchez, Silvia Jesús, Sílvia Preckler, Silvia Rodrigo‐Herrero, Susana Diego, Alessandro Vacca, Fausto Roveta, Nicola Salvadori, Elena Chipi, Henning Boecker, Christoph Laske, Robert Perneczky, Costas A. Anastasiou, Daniel Janowitz, Rainer Malik, Anna Anastasiou, Sara López‐García, Anna Antonell, Kalina Mihova, Diyana Belezhanska, Heike Weber, Silvia Kochen, Patricia Solís, Nancy Medel, Julieta Lisso, Zulma Sevillano, Daniel Gustavo Politis, Valeria Cores, Carolina Cuesta, Cecilia Ortíz, Juan Ignacio Bacha, Mario Rios, Aldo Saenz, Mariana Sanchez Abalos, Eduardo Köhler, Dana Lis Palacio, Ignacio Etchepareborda, Matias Köhler, Gisela V. Novack, Federico Ariel Prestia, Pablo Galeano, Eduardo M. Castaño, Sandra Germani, Carlos Reyes Toso, Matias Rojo, Carlos A. Ingino, Carlos A. Mangone, Sebastiaan Engelborghs, Fabrizio Tagliavini, Lucia Farotti, Chiara Fenoglio, Geert Jan Biessels, Seth Love, Christine Van Broeckhoven, David C. Rubinsztein, Stefan Teipel, Nathalie Fiévet, Vincent Deramecourt, Charlotte Forsell, Håkan Thonberg, Maria Bjerke, Ellen De Roeck, Nicholas G. Martin, Natividad Olivar, Mohsen Ghanbari, Perminder S. Sachdev, Karen A. Mather, M. Arfan Ikram, Tsolaki Magda, Cornelia M. van Duijn, Rebecca Sims, N. Aguilera, Estefanía Burgos Alarcón, Marie‐Annick Buendia, Amanda Cano, Arturo Corbatón Anchuelo, Itziar de Rojas, S. Diego, M. Guitart, A González-Péerez, A. Lafuente, Olalla Maroñas, Elisabeth Martin, M.T.M. Martinez, M. Moreno, Raúl Núñez‐Llaves, C. Olivé, E. Pelejà, ME Sáez, Manuel Serrano‐Ríos, L Táarraga, MD Alonso, G. Amer-Ferrer, M. Antequera, Carmen Antúnez, M. Bernal, MJ Bullido, Burguera Ja, MJ Casajeros, JM Cruz-Gamero, Marian M. de Pancorbo, Emilio Franco, JM García-Alberca, S. García Madrona, S. Hevilla, MA Labrador Espinosa, A. Legaz, A Lleóo, A Lóopez de Munáin, Salvadora Manzanares, Juan Marín-Muñoz, T Marín, B. Martínez, Carmen Martı́nez, Vicente Martı́nez, A Martínez-Lage Álvarez, J Péerez Tur, María Teresa Periñán, G. Piñol Ripoll, A Ráabano, Diego Real de Asúa, S. Rodrigo, JL Royo, R. Sanchez del Valle Díaz, Pascual Sánchez‐Juan, Isabel Sastre, MP Vicente, L. Vivancos, Shahram Bahrami, Ingunn Bosnes, Per Selnes, Sverre Bergh, Jacques Epelbaum, Didier Hannequin, Dominique Campion, Christophe Tzourio, Vincent Dermecourt, Alexis Brice, Bruno Dubois, Karen Ritchie, Amy L. Williams, Charlene Thomas, Chloe Davies, Will Nash, Kimberley Dowzell, Atahualpa Castillo-Morales, Mateus Bernardo-Harrington, James Turton, Jenny Lord, Kristelle Brown, Emma Vardy, Elizabeth Fisher, Jason D. Warren, Natalie S. Ryan, Rita Guerreiro, James Uphill, Reinhard Heun, Heike Kölsch, Britta Schürmann, ndré Lacour, Christine Herold, Janet Johnston, Yogen Patel, Angela Hodges, Tim Becker, Donald Warden, Gordon Wilcock, Robert Clarke, Yoav Ben‐Shlomo, Nigel M. Hooper, Stuart Pickering‐Brown, Rebecca Sussams, Andrew Singleton, Isabella Heuser, Dmitriy Drichel, Norman Klopp, Markus M. Nöthen, Manuel Mayhaus, Sabrina Pinchler, Thomas Feulner, Wei Gu, Hendrik den Bussche, Michael Hüll, Lutz Frölich, H‐Erich Wichmann, Karl‐Heinz Jöckel, John Kauwe, John C. Morris, Kevin H. Mayo, Michael J. Owen, Elaine Guo Yan Chew, Sun Ju Chung, Rong Peng, Yinxia Chao, Louis Tan, Moses Tandiono, Ebonne Ng, Kumar‐M. Prakash, Wing‐Lok Au, Wee-Yang Meah, Shi Qi Mok, Azlina Ahmad‐Annuar, Anne Chan, Ling Chen, Yongping Chen, Beom S. Jeon, Lulu Jiang, Jia Lun Lim, Juei‐Jueng Lin, Chun‐Feng Liu, Chengjie Mao, Vincent Mok, Zhong Pei, Huifang Shang, Changhe Shi, Kyuyoung Song, Ai Huey Tan, Yih‐Ru Wu, Yuming Xu, Renshi Xu, Yaping Yan, Jing Yang, Bao Rong Zhang, Woon‐Puay Koh, Shen‐Yang Lim, Chiea Chuen Khor, Jianjun Liu
Bibliographic record
VenueProceedings of the National Academy of Sciences · 2023
Typearticle
Languageen
FieldNeuroscience
TopicNeuroinflammation and Neurodegeneration Mechanisms
Canadian institutionsOntario Brain InstituteMontreal Neurological Institute and HospitalUniversity of TorontoUniversity Health NetworkMcGill UniversityOccupational Cancer Research Centre
FundersNational Institute on AgingRIKENUniversitätsklinikum KölnAlzheimer's AssociationFondazione I.R.C.C.S. Istituto Neurologico Carlo BestaUniversität zu KölnGöteborgs UniversitetUniversity of OxfordSahlgrenska UniversitetssjukhusetUK Dementia Research InstituteUniversitetet i OsloUniversity of TorontoEU Joint Programme – Neurodegenerative Disease ResearchInstitut National de la Santé et de la Recherche MédicaleNational Institute of Neurological Disorders and StrokeSahlgrenska AkademinVetenskapsrådetDevelopment of Innovative Strategies for a Transdisciplinary approach to ALZheimer's diseaseJapan Agency for Medical Research and DevelopmentDeutsches Zentrum für Neurodegenerative ErkrankungenUniversidade de AveiroCardiff UniversityVästra GötalandsregionenUniversity of BristolMedical Research CouncilMichael J. Fox Foundation for Parkinson's Research
KeywordsHuman leukocyte antigenParkinson's diseaseLocus (genetics)Immune systemDiseaseBiologyNeuroscienceImmunologyGeneticsMedicineGeneAntigenPathology
Abstract
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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 machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.001
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.001
Threshold uncertainty score0.005
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 head0.060
GPT teacher head0.300
Teacher spread0.241 · 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 source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
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
Citations51
Published2023
Admission routes2
Has abstractyes