Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Le Guen, Yann, Luo, Guo, Ambati, Aditya, Damotte, Vincent, Jansen, Iris, Yu, Eric, Nicolas, Aude, de Rojas, Itziar, Peixoto Leal, Thiago, Miyashita, Akinori, Bellenguez, Céline, Lian, Michelle Mulan, Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier-Boley, Benjamin, Naito, Tatsuhiko, Küçükali, Fahri, Talyansky, Seth D., Yogeshwar, Selina Maria, Sempere, Vicente, Satake, Wataru, Alvarez, Victoria, Arosio, Beatrice, Belloy, Michael E., Benussi, Luisa, Boland, Anne, Borroni, Barbara, Bullido, María J., Caffarra, Paolo, Clarimon, Jordi, Daniele, Antonio, Darling, Daniel, Debette, Stéphanie, Deleuze, Jean-François, Dichgans, Martin, Dufouil, Carole, During, Emmanuel, Düzel, Emrah, Galimberti, Daniela, Garcia-Ribas, Guillermo, García-Alberca, José María, García-González, Pablo, Giedraitis, Vilmantas, Goldhardt, Oliver, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jung, Yoo Jin, Jürgen, Deckert, Kern, Silke, Kuulasmaa, Teemu, Lee, Kun Ho, Lin, Ling, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Boada, Mercè, Mir, Pablo, Moebus, Susanne, Moreno, Fermin, Nacmias, Benedetta, Nicolas, Gael, Niida, Shumpei, Nordestgaard, Børge G., Papenberg, Goran, Papma, Janne, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peters, Oliver, Pijnenburg, Yolande A. L., Piñol-Ripoll, Gerard, Popp, Julius, Porcel, Laura Molina, Puerta, Raquel, Pérez-Tur, Jordi, Rainero, Innocenzo, Ramakers, Inez, Real, Luis M., Riedel-Heller, Steffi, Rodriguez-Rodriguez, Eloy, Ross, Owen A., Luís Royo, Jose, Rujescu, Dan, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Skoog, Ingmar, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Sánchez-Valle, Raquel, Tan, Eng-King, Tegos, Thomas, Teunissen, Charlotte, Thomassen, Jesper Qvist, Tremolizzo, Lucio, Vyhnalek, Martin, Verhey, Frans, Waern, Margda, Wiltfang, Jens, Zhang, Jing, Zetterberg, Henrik, Blennow, Kaj, He, Zihuai, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., Andreassen, Ole A., Van Duin, Cornelia, Tsolaki, Magda, Sánchez-Juan, Pascual, Frikke-Schmidt, Ruth, Sleegers, Kristel, Toda, Tatsushi, Zettergren, Anna, Ingelsson, Martin, Okada, Yukinori, Rossi, Giacomina, Hiltunen, Mikko, Gim, Jungsoo, Ozaki, Kouichi, Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, Foo, Jia Nee, van der Flier, Wiesje, Ikeuchi, Takeshi, Ramirez, Alfredo, Mata, Ignacio, Ruiz, Agustín, Gan-Or, Ziv, Lambert, Jean-Charles, Greicius, Michael D., Mignot, Emmanuel, Bellenguez, Céline, Küçükali, Fahri, Jansen, Iris, Andrade, Victor, Moreno-Grau, Sonia, Amin, Najaf, Grenier-Boley, Benjamin, Campos-Martin, Rafael, Holmans, Peter A., Boland, Anne, Kleineidam, Luca, Damotte, Vincent, van der Lee, Sven J., Kuulasmaa, Teemu, de Rojas, Itziar, Yaqub, Amber, Prokic, Ivana, Costa, Marcos R, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcón-Martín, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Álvarez, Victoria, Armstrong, Nicola J., Anthoula, Tsolaki, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Arias Pastor, Alfonso, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Belén Pastor, Ana, Benussi, Luisa, Berr, Claudine, Besse, Céline, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Mercè, Borroni, Barbara, Boschi, Silvia, Bossù, Paola, Bråthen, Geir, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J., Ignacio Brusco, Luis, Buiza-Rueda, Dolores, BÛrger, Katharina, Burholt, Vanessa, Calero, Miguel, Chene, Geneviève, Carracedo, Ángel, Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A.H.R., Clarimon, Jordi, Clark, Christopher, Conti, Elisa, Corma-Gómez, Anaïs, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-François, de Deyn, Peter Paul, Debette, Stéphanie, Deckert, Jürgen, del Ser, Teodoro, Denning, Nicola, Dichgans, Martin, Diehl-Schmid, Janine, Diez-Fairen, Mónica, Dionigi Rossi, Paolo, Djurovic, Srdjan, Duron, Emmanuelle, 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A., Skrobot, Olivia, Soininen, Hilkka, Solfrizzi, Vincenzo, Solomon, Alina, Sorbi, Sandro, Sotolongo-Grau, Oscar, Spalletta, Gianfranco, Spottke, Annika, Squassina, Alessio, Stordal, Eystein, Pablo Tartan, Juan, Tárraga, Lluís, Tesí, Niccolo, Thalamuthu, Anbupalam, Thomas, Tegos, Traykov, Latchezar, Tremolizzo, Lucio, Tybjærg-Hansen, Anne, Uitterlinden, Andre, Ullgren, Abbe, Ulstein, Ingun, Valero, Sergi, van der Lugt, Aad, Van Dongen, Jasper, van Rooij, Jeroen, van Swieten, John, Vandenberghe, Rik, Verhey, Frans, Vidal, Jean-Sébastien, Vogelgsang, Jonathan, Vyhnalek, Martin, Wagner, Michael, Wallon, David, Weinhold, Leonie, Wiltfang, Jens, Windle, Gill, Woods, Bob, Yannakoulia, Mary, Zulaica, Miren, Laczo, Jan, Matoska, Vaclav, Serpente, Maria, Assogna, Francesca, Piras, Fabrizio, Piras, Federica, Ciullo, Valentina, Shofany, Jacob, Ferrarese, Carlo, Andreoni, Simona, Sala, Gessica, Paola Zoia, Chiara, Del Zompo, Maria, Benussi, Alberto, Bastiani, Patrizia, Takalo, Mari, Natunen, 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ORCID: https://orcid.org/0000-0001-7073-2379, Owen, Michael J. 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A., Pastor, P., Péerez Tur, J., Periñán-Tocino, T., Pineda-Sánchez, R., Piñol Ripoll, G., Ráabano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J.L., Ruiz, A., Sanchez del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Sotolongo-Grau, O., Valero, S., Vicente, M.P., Vigo-Ortega, R., Vivancos, L., Shadrin, Alexey A., Bahrami, Shahram, Rongve, Arvid, Bråthen, Geir, Bosnes, Ingunn, Stordal, Eystein, Athanasiu, Lavinia, Selnes, Per, Saltvedt, Ingvild, Sando, Sigrid B., Bergh, Sverre, Ulstein, Ingun, Djurovic, Srdjan, Fladby, Tormod, Aarsland, Dag, Selbæk, Geir, Andreassen, Ole A., Bellenguez, Céline, Grenier-Boley, Benjamin, Epelbaum, Jacques, Wallon, David, Hannequin, Didier, Pasquier, Florence, Berr, Claudine, Dartigues, Jean-Francois, campion, Dominique, Tzourio, Christophe, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Dubois, Bruno, Ritchie, Karen, Amouyel, Phillippe, Lambert, Jean-Charles, Harold, Denise, Hollingworth, Paul, Sims, Rebecca, Gerrish, Amy, Denning, Nicola, Williams, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Davies, Chloe, Luckcuck, Lauren, Nash, William, Dowzell, Kimberley, Castillo Morales, Atahualpa, Bernardo-Harrington, Mateus, Kehoe, Patrick, Hoffmann, Per, Love, Seth, Turton, James, Lord, Jenny, Brown, Kristelle, Morgan, Kevin, Vardy, Emma, Fisher, Elizabeth, Warren, Jason D., Schott, Jonathan M., Rossor, Martin, Ryan, Natalie S., Fox, Nick C., Guerreiro, Rita, Mead, Simon, Uphill, James, Collinge, John, Lupton, Michelle, Al-Chalabi, Ammar, Shaw, Christopher E., Bass, Nick, Abraham, Richard, Heun, Reinhard, Kölsch, Heike, Schürmann, Britta, Jessen, Frank, Maier, Wolfgang, Lacour, ndré, Herold, Christine, Lovestone, Simon, McGuinness, Bernadette, Craig, David, Johnston, Janet A., Gill, Michael, Passmore, Peter, Todd, Stephen, Powell, John, Proitsi, Petra, Patel, Yogen, Hodges, Angela, Becker, Tim, David Smith, A., Warden, Donald, Wilcock, Gordon, Clarke, Robert, Lynch, Aoibhinn, Lawlor, Brian, Gill, Michael, McQuillin, Andrew, Livingston, Gill, Hardy, John, Rubinsztein, David C., Brayne, Carol, Gwilliam, Rhian, Deloukas, Panagiotis, Ben-Shlomo, Yoav, Mann, David, Hooper, Nigel M., Pickering-Brown, Stuart, Holmes, Clive, Sussams, Rebecca, Warner, Nick, Bayer, Anthony, Singleton, Andrew B., Hartmann, Annette M., Rujescu, Dan, Giegling, Ina, Hampel, Harald, Dichgans, Martin, Heuser, Isabella, Drichel, Dmitriy, Klopp, Norman, Nöthen, Markus M., Mayhaus, Manuel, Riemenschneider, Matthias, Pinchler, Sabrina, Feulner, Thomas, Gu, Wei, den Bussche, Hendrik, Scherer, Martin, Wiltfang, Jens, Kornhuber, Johannes, Hüll, Michael, Frölich, Lutz, Wichmann, H-Erich, Jöckel, Karl-Heinz, Moebus, Susanne, Riedel-Heller, Steffi, Kauwe, John, Morris, John, Mayo, Kevin, Tsolaki, Magda, O'Donovan, Michael, Jones, Lesley, Owen, Michael, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Ramirez, Alfredo, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Williams, Julie, Foo, Jia Nee, Chew, Elaine Guo Yan, Chung, Sun Ju, Peng, Rong, Chao, Yinxia, Tan, Louis C.S., Tandiono, Moses, Lian, Michelle M., Ng, Ebonne Y., Prakash, Kumar-M., Au, Wing-Lok, Meah, Wee-Yang, Mok, Shi Qi, Annuar, Azlina Ahmad, Chan, Anne Y.Y., Chen, Ling, Chen, Yongping, Jeon, Beom S., Jiang, Lulu, Lim, Jia Lun, Lin, Juei-Jueng, Liu, Chunfeng, Mao, Chengjie, Mok, Vincent, Pei, Zhong, Shang, Hui-Fang, Shi, Chang-He, Song, Kyuyoung, Tan, Ai Huey, Wu, Yih-Ru, Xu, Yu-ming, Xu, Renshi, Yan, Yaping, Yang, Jing, Rong Zhang, Bao, Koh, Woon-Puay, Lim, Shen-Yang, Khor, Chiea Chuen, Liu, Jianjun and Tan, Eng-King 2023. Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes. Proceedings of the National Academy of Sciences 120 (36) , e2302720120. 10.1073/pnas.2302720120

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	19 October 2023
Date of Acceptance:	18 May 2023
Last Modified:	05 Jan 2024 08:18
URI:	https://orca.cardiff.ac.uk/id/eprint/163289

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