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
Archive ouverte
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 | Yogeshwar, Selina Maria | Sempere, Vicente | Satake, Wataru | Alvarez, Victoria | Arosio, Beatrice | Belloy, Michael | Benussi, Luisa | Boland, Anne | Borroni, Barbara | Bullido, María | 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 | Papenberg, Goran | Papma, Janne | Parnetti, Lucilla | Pasquier, Florence | Pastor, Pau | Peters, Oliver | Pijnenburg, Yolande | Piñol-Ripoll, Gerard | Popp, Julius | Porcel, Laura Molina | Puerta, Raquel | Pérez-Tur, Jordi | Rainero, Innocenzo | Ramakers, Inez | Real, Luis | Riedel-Heller, Steffi | Rodriguez-Rodriguez, Eloy | Ross, Owen | 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 | Amouyel, Philippe | Jessen, Frank | Kehoe, Patrick | Andreassen, Ole | 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 | Foo, Jia Nee | van der Flier, Wiesje | Ikeuchi, Takeshi | Ramirez, Alfredo | Mata, Ignacio | Ruiz, Agustín | Gan-Or, Ziv | Lambert, Jean-Charles | Greicius, Michael | Mignot, Emmanuel | Andrade, Victor | Moreno-Grau, Sonia | Amin, Najaf | Campos-Martin, Rafael | Holmans, Peter | Kleineidam, Luca | van der Lee, Sven | Yaqub, Amber | Prokic, Ivana | Costa, Marcos | Chapuis, Julien | Ahmad, Shahzad | Aarsland, Dag | Garcia-Gonzalez, Pablo | Abdelnour, Carla | Alarcón-Martín, Emilio | Alcolea, Daniel | Alegret, Montserrat | Alvarez, Ignacio | Álvarez, Victoria | Armstrong, Nicola | Anthoula, Tsolaki | Appollonio, Ildebrando | Arcaro, Marina | Archetti, Silvana | Arias Pastor, Alfonso | Athanasiu, Lavinia | Bailly, Henri | Banaj, Nerisa | Baquero, Miquel | Belén Pastor, Ana | Berr, Claudine | Besse, Céline | Bessi, Valentina | Binetti, Giuliano | Bizarro, Alessandra | Blesa, Rafael | Boschi, Silvia | Bossù, Paola | Bråthen, Geir | Bresner, Catherine | Brodaty, Henry | Brookes, Keeley | 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. | Clark, Christopher | Conti, Elisa | Corma-Gómez, Anaïs | Costantini, Emanuele | Custodero, Carlo | Daian, Delphine | Dalmasso, Maria Carolina | Dardiotis, Efthimios | Dartigues, Jean-François | de Deyn, Peter Paul | Deckert, Jürgen | del Ser, Teodoro | Denning, Nicola | Diehl-Schmid, Janine | Diez-Fairen, Mónica | Dionigi Rossi, Paolo | Djurovic, Srdjan | Duron, Emmanuelle | Escott-Price, Valentina | Espinosa, Ana | Ewers, Michael | Fernández-Fuertes, Marta | Ferreira, Catarina | Ferri, Evelyn | Fin, Bertrand | Fischer, Peter | Fladby, Tormod | Fließbach, Klaus | Fortea, Juan | Fostinelli, Silvia | Fox, Nick | Franco-Macías, Emlio | Frank-García, Ana | Froelich, Lutz | Maria García-Alberca, Jose | Garcia-Madrona, Sebastian | Ghidoni, Roberta | Giegling, Ina | Giorgio, Giaccone | González-Pérez, Antonio | Grande, Giulia | Green, Emma | Grimmer, Timo | Guetta-Baranes, Tamar | Haapasalo, Annakaisa | Hadjigeorgiou, Georgios | Hampel, Harald | Hardy, John | Hartmann, Annette | Harwood, Janet | Helisalmi, Seppo | Heneka, Michael | Hernández, Isabel | Herrmann, Martin | Hoffmann, Per | Holmes, Clive | Huerto Vilas, Raquel | Hulsman, Marc | Johansson, Charlotte | Kilander, Lena | Kinhult Ståhlbom, Anne | Kivipelto, Miia | Koivisto, Anne | Kornhuber, Johannes | Kosmidis, Mary | Lage, Carmen | Laukka, Erika | Lauria, Alessandra | Lehtisalo, Jenni | Lerch, Ondrej | Lleó, Alberto | de Munain, Adolfo Lopez | Löwemark, Malin | Luckcuck, Lauren | Macías, Juan | Macleod, Catherine | Maier, Wolfgang | Mangialasche, Francesca | Marco, Spallazzi | Marquié, Marta | Marshall, Rachel | Martín Montes, Angel | Martínez Rodríguez, Carmen | Mead, Simon | Medina, Miguel | Meggy, Alun | Mendoza, Silvia | Menéndez-González, Manuel | Mol, Merel | Molina-Porcel, Laura | Montrreal, Laura | Morelli, Laura | Morgan, Kevin | Möthen, Markus | Muchnik, Carolina | Ngandu, Tiia | Olaso, Robert | Orellana, Adelina | Orsini, Michela | Ortega, Gemma | Padovani, Alessandro | Paolo, Caffarra | Pérez-Cordón, Alba | Pericard, Pierre | Pijnenburg, Yolande A.L. | Pineda, Juan | Pisanu, Claudia | Polak, Thomas | Posthuma, Danielle | Priller, Josef | Quenez, Olivier | Quintela, Inés | Qvist Thomassen, Jesper | Rábano, Alberto | Reinders, Marcel J.T. | Riederer, Peter | Roberto, Natalia | Rongve, Arvid | Rosas Allende, Irene | Rosende-Roca, Maitée | Luis Royo, Jose | Rubino, Elisa | Eugenia Sáez, María | Sakka, Paraskevi | Saltvedt, Ingvild | Sanabria, Ángela | Sánchez-Arjona, María Bernal | Sanchez-Garcia, Florentino | Sánchez Juan, Pascual | Sando, Sigrid | Scamosci, Michela | Scarpini, Elio | Scherer, Martin | Schmid, Matthias | Schott, Jonathan | Selbæk, Geir | Shadrin, Alexey | Skrobot, Olivia | Soininen, Hilkka | Solomon, Alina | Sorbi, Sandro | Sotolongo-Grau, Oscar | Spottke, Annika | Stordal, Eystein | Pablo Tartan, Juan | Tárraga, Lluís | Tesí, Niccolo | Thalamuthu, Anbupalam | Thomas, Tegos | Traykov, Latchezar | Tybjærg-Hansen, Anne | Uitterlinden, Andre | Ullgren, Abbe | Ulstein, Ingun | Valero, Sergi | van der Lugt, Aad | van Dongen, Jasper | van Rooij, Jeroen | Vandenberghe, Rik | Vidal, Jean-Sébastien | Vogelgsang, Jonathan | Wagner, Michael | Wallon, David | Weinhold, Leonie | 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, Teemu | Laatikainen, Tiina | Tuomilehto, Jaakko | Antikainen, Riitta | Strandberg, Timo | Lindström, Jaana | Peltonen, Markku | Abraham, Richard | Al-Chalabi, Ammar | Bass, Nicholas | Brayne, Carol | Brown, Kristelle | Collinge, John | Craig, David | Deloukas, Pangiotis | Gerrish, Amy | Gill, Michael | Gwilliam, Rhian | Harold, Denise | Hollingworth, Paul | Johnston, Jarret | Jones, Lesley | Lawlor, Brian | Livingston, Gill | Lovestone, Simon | Lupton, Michelle | Lynch, Aoibhinn | Mann, David | Mcguinness, Bernadette | Mcquillin, Andrew | O’donovan, Michael | Owen, Michael | Passmore, Peter | Powell, John | Proitsi, Petra | Rossor, Martin | Shaw, Christopher | David Smith, A. | Gurling, Hugh | Todd, Stephen | Mummery, Catherine | Ryan, Nathalie | Lacidogna, Giordano | Adarmes-Gómez, Ad | Mauleón, Ana | Pancho, Ana | Gailhajenet, Anna | Lafuente, Asunción | Macias-García, D | Martín, Elvira | Pelejà, Esther | Carrillo, F | Sastre Merlín, Isabel | Garrote-Espina, L | Vargas, Liliana | Carrion-Claro, M | Marín, M | Labrador, Ma | Buendia, Mar | Dolores Alonso, María | Guitart, Marina | Moreno, Mariona | Ibarria, Marta | Periñán, Mt | Aguilera, Nuria | Gómez-Garre, P | Cañabate, Pilar | Escuela, R | Pineda-Sánchez, R | Vigo-Ortega, R | Jesús, S | Preckler, Silvia | Rodrigo-Herrero, Silvia | Diego, Susana | Vacca, Alessandro | Roveta, Fausto | Salvadori, Nicola | Chipi, Elena | Boecker, Henning | Laske, Christoph | Perneczky, Robert | Anastasiou, Costas | Janowitz, Daniel | Malik, Rainer | Anastasiou, Anna | López-García, Sara | Antonell, Anna | Yonkova Mihova, Kalina | Belezhanska, Diyana | Weber, Heike | Kochen, Silvia | Solis, Patricia | Medel, Nancy | Lisso, Julieta | Sevillano, Zulma | Politis, Daniel | Cores, Valeria | Cuesta, Carolina | Ortiz, Cecilia | Ignacio Bacha, Juan | Rios, Mario | Saenz, Aldo | Sanchez Abalos, Mariana | Kohler, Eduardo | Lis Palacio, Dana | Etchepareborda, Ignacio | Kohler, Matias | Novack, Gisela | Ariel Prestia, Federico | Galeano, Pablo | Castaño, Eduardo | Germani, Sandra | Reyes Toso, Carlos | Rojo, Matias | Ingino, Carlos | Mangone, Carlos | Engelborghs, Sebastiaan | Fabrizio, Tagliavini | Fallgaard Nielsen, Sune | Farotti, Lucia | Fenoglio, Chiara | Jan Biessels, Geert | Love, Seth | van Broeckhoven, Christine | Rubinsztein, David | Teipel, Stefan | Fievet, Nathalie | Deramecourt, Vincent | Forsell, Charlotte | Thonberg, Håkan | Bjerke, Maria | de Roeck, Ellen | Teresa Martínez-Larrad, María | Olivar, Natividad | Ghanbari, Mohsen | Sachdev, Perminder | Mather, Karen | Arfan Ikram, M. | Magda, Tsolaki | van Duijn, Cornelia | Aguilera, N | Alarcon, E | Alegret, M | Boada, M | Buendia, M | Cano, A | Cañabate, P | Carracedo, A | Corbatón-Anchuelo, A | de Rojas, I | Diego, S | Espinosa, A | Gailhajenet, A | García-González, P | Guitart, M | González-Péerez, A | Ibarria, M | Lafuente, A | Macias, J | Maroñas, O | Martín, E | Martínez, Mt | Marquié, M | Montrreal, L | Moreno-Grau, S | Moreno, M | Nuñez-Llaves, R. | Olivé, C | Orellana, A | Ortega, G | Pancho, A | Pelejà, E | Pérez-Cordon, A | Pineda, Ja | Puerta, R | Preckler, S | Quintela, I | Real, Lm | Rosende-Roca, M | Ruiz, A | Sáez, Me | Sanabria, A | Serrano-Rios, M | Sotolongo-Grau, O | Táarraga, L | Valero, S | Vargas, L | Alarcón-Martín, E | Alonso, Md | Álvarez, I | Álvarez, V | Amer-Ferrer, G | Antequera, M | Antúnez, C | Baquero, M | Bernal, M | Blesa, R | Buiza-Rueda, D | Bullido, Mj | Burguera, Ja | Calero, M | Carrión-Claro, M | Casajeros, Mj | Clarimón, J | Cruz-Gamero, Jm | de Pancorbo, Mm | del Ser, T | Diez-Fairen, M | Fortea, J | Franco, E | Frank-García, A | García-Alberca, Jm | Garcia Madrona, S | Garcia-Ribas, G | Hevilla, S | Labrador Espinosa, Ma | Lage, C | Legaz, A | Lleóo, A | Lóopez de Munáin, A | López-García, S | Manzanares, S | Marín-Muñoz, J | Marín, T | Martín Montes, A | Martínez, B | Martínez, C | Martínez, V | Martínez-Lage Álvarez, A | Medina, M | Mendioroz Iriarte, M | Menéndez-González, M | Mir, P | Pastor, P | Péerez Tur, J | Periñán-Tocino, T | Piñol Ripoll, G | Ráabano, A | Real de Asúa, D | Rodrigo, S | Rodríguez-Rodríguez, E | Royo, Jl | Sanchez del Valle Díaz, R | Sánchez-Juan, P | Sastre, I | Vicente, Mp | Vivancos, L | Bahrami, Shahram | Bosnes, Ingunn | Selnes, Per | Bergh, Sverre | Epelbaum, Jacques | Hannequin, Didier | Dartigues, Jean-Francois | Campion, Dominique | Tzourio, Christophe | Dermecourt, Vincent | Brice, Alexis | Dubois, Bruno | Ritchie, Karen | Amouyel, Phillippe | Williams, Amy | Thomas, Charlene | Davies, Chloe | Nash, William | Dowzell, Kimberley | Castillo Morales, Atahualpa | Bernardo-Harrington, Mateus | Turton, James | Lord, Jenny | Vardy, Emma | Fisher, Elizabeth | Warren, Jason | Ryan, Natalie | Guerreiro, Rita | Uphill, James | Bass, Nick | Heun, Reinhard | Kölsch, Heike | Schürmann, Britta | Lacour, Ndré | Herold, Christine | Johnston, Janet | Patel, Yogen | Hodges, Angela | Becker, Tim | Warden, Donald | Wilcock, Gordon | Clarke, Robert | Deloukas, Panagiotis | Ben-Shlomo, Yoav | Hooper, Nigel | Pickering-Brown, Stuart | Sussams, Rebecca | Warner, Nick | Bayer, Anthony | Singleton, Andrew | Heuser, Isabella | Drichel, Dmitriy | Klopp, Norman | Nöthen, Markus | Mayhaus, Manuel | Riemenschneider, Matthias | Pinchler, Sabrina | Feulner, Thomas | Gu, Wei | den Bussche, Hendrik | Hüll, Michael | Frölich, Lutz | Wichmann, H-Erich | Jöckel, Karl-Heinz | Kauwe, John | Morris, John | Mayo, Kevin | Chew, Elaine Guo Yan | Chung, Sun Ju | Peng, Rong | Chao, Yinxia | Tan, Louis Cs | Tandiono, Moses | Lian, Michelle | Ng, Ebonne | Prakash, Kumar-M. | Au, Wing-Lok | Meah, Wee-Yang | Mok, Shi Qi | Annuar, Azlina Ahmad | Chan, Anne Yy | Chen, Ling | Chen, Yongping | Jeon, Beom | 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
Edité par
CCSD ; National Academy of Sciences -
International audience.
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.
