Mayo Clinic - AuthorCitation

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

Guen, Yann Le , Luo, Guo , Damotte, Vincent , Jansen, Iris E. , Nicolas, Aude , Rojas, Itziar de, Bellenguez, Céline , Lian, Michelle Mulan , Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier‐Boley, Benjamin , Naito, Tatsuhiko , Talyansky, Seth D., Yogeshwar, Selina , Sempere, Vicente Peris, Satake, Wataru , Álvarez, Victoria , Arosio, Beatrice , Boland, Anne , Daniele, Antonio , Darling, D.H., Dichgans, Martin , Dufouil, Carole , Düzel, Emrah , García‐Ribas, Guillermo, García‐Alberca, José María , García-González, Pablo, Giedraitis, Vilmantas , Graff, Caroline , Grünblatt, Edna , Hausner, Lucrezia , Jung, Yoo Jin , Deckert, Jürgen, Kern, Silke , Kuulasmaa, Teemu , Lee, Kun Ho , Lin, Ling , Masullo, Carlo , Mehrabian, Shima , Mendonça, Alexandre de , Boada, Merçé , Mir, Pablo , Moreno, Fermín , Nicolas, Gaël , Niida, Shumpei , Nordestgaard, Børge G. , Papenberg, Goran, Papma, Janne M., Pástor, Pau , Peters, Oliver , Popp, Julius , Molina‐Porcel, Laura , Puerta, Raquel , Pérez‐Tur, Jordi , Ramakers, Inez H.G.B. , Real, Luís Miguel , Riedel‐Heller, Steffi G. , Rodríguez‐Rodríguez, Eloy , Ross, Owen A. , Scarmeas, Nikolaos , Schneider, Anja , Solfrizzi, Vincenzo , Spalletta, Gianfranco , Tan, Eng‐King , Tegos, Thomas, Thomassen, Jesper Qvist , Tremolizzo, Lucio , Verhey, Frans, EADB, group, GR@ACE study, DemGene, EADI, GERAD, Blennow, Kaj , He, Zihuai , Jessen, Frank , Kehoe, Patrick G. , Duin, Cornelia van, Sánchez‐Juan, Pascual , Zettergren, Anna , Okada, Yukinori , Rossi, Giacomina, Gim, Jungsoo , Sims, Rebecca, Ramı́rez, Alfredo , Lambert, Jean‐Charles , Greicius, Michael D. , Mignot, Emmanuel , Moreno–Grau, Sonia , Rojas, Itziar de, Prokic, Ivana, Aarsland, Dag, García‐González, Pablo , Abdelnour, Carla , Armstrong, Nicola J. , Anthoula, Tsolaki, Archetti, Silvana, Pastor, Alfonso Arias, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa , Baquero, Miquel , Pastor, Ana Belén , Besse, Céline , Bizarro, Alessandra, Blesa, Rafael , Bossù, Paola , Brusco, Luis Ignacio , Buiza‐Rueda, Dolores, Bürger, Katharina , Burholt, Vanessa, Cecchetti, Roberta, Chillotti, Caterina , Ciccone, Simona, Claassen, Jurgen A.H.R., Clark, Christopher , Costantini, Emanuele Maria , Daian, Delphine , Dartigues, Jean‐François, Escott-Price, Valentina, Ewers, Michael , Fernández‐Fuertes, Marta , Ferreira, Catarina B. , Fin, Bertrand, Fließbach, Klaus , Franco-Macías, Emlio, García-González, Pablo, García‐Madrona, Sebastián, Giegling, Ina, Giorgio, Giaccone, González-Pérez, Antonio, Grande, Giulia , Green, Emma , Grimmer, Timo, Hardy, John, Hartmann, Annette M. , Harwood, Janet , Helisalmi, Seppo , Hernández, Isabel, Hoffmann, Per, Vilas, Raquel Huerto, Hulsman, Marc , Johansson, Charlotte , Kilander, Lena, Ståhlbom, Anne Kinhult, Koivisto, Anne M. , Lage, Carmen , Lerch, Ondřej , Munain, Adolfo Lopez de, Löwemark, Malin, Luckcuck, Lauren, Maier, Wolfgang, Marco, Spallazzi, Montes, Ángel Martín, Rodríguez, Carmen Martínez, Meggy, Alun, Mendoza, Silvia, Moebus, Susanne, Morelli, Laura , Möthen, Markus M., Muchnik, Carolina , Orsini, Michela, Péricard, Pierre , Piñol-Ripoll, Gerard, Polak, Thomas, Quenez, Olivier , Rábano, Alberto , Ramakers, Inez, Riederer, Peter, Rongve, Arvid, Allende, Irene Rosas, Rujescu, Dan, Sakka, Paraskevi , Sánchez‐Arjona, María Bernal, Sando, Sigrid Botne , Scamosci, Michela, Scherbaum, Norbert, Scherer, Martin, Schott, Jonathan M., Shadrin, Alexey A, Skrobot, Olivia Anna, Solfrizzi, Vincenzo, Spottke, Annika , Stordal, Eystein , Tartan, Juan Pablo, Traykov, Latchezar , Tybjærg‐Hansen, Anne, Ullgren, Abbe, Ulstein, Ingun, Dongen, Jasper Van , Wallon, David, Windle, Gill, Woods, Bob , Zulaica, Miren , Laczó, Jan , Maťoška, Václav , Piras, Federica, Ciullo, Valentina , Shofany, Jacob, Andreoni, Simona, Zompo, Maria Del, Bastiani, Patrizia, Natunen, Teemu , Antikaínen, Riitta , Abraham, Richard, Al-Chalabi, Ammar, Brayne, Carol, Brown, Kristelle S., Collinge, John, Craig, David W. , Deloukas, Pangiotis, Gerrish, Amy, Gwilliam, Rhian, Hardy, John , Hollingworth, Paul, Johnston, Jarret A., Jones, Lesley , Lawlor, Brian, Lynch, Aoibhinn, McQuillin, Andrew, Owen, Michael J., Passmore, Peter , Proitsi, Petra, Rossor, Martin, Gurling, Hugh, Todd, Stephen, Mummery, Catherine J. , Ryan, Nathalie, Lacidogna, Giordano , Adarmes-Gómez, Ad, Mauleón, Ana , Pancho, Ana, Gailhajenet, A., Lafuente, Asunción, Martín, Elvira, Pelejà, Esther, Carrillo, F, Merlín, Isabel Sastre, Garrote-Espina, L. , Carrión‐Claro, Mario, Marín, María Esmeralda Arreola , Labrador, Ma, Buendía, Mar, Guitart, Marina, Moreno, Mariona, Ibarria, Marta, Periñán, Mt, Aguilera, Núria , Gómez-Garre, P, Escuela, R, Pineda-Sanchez, R., Vigo-Ortega, R, Preckler, Sílvia , Rodrigo‐Herrero, Silvia , Diego, Susana, Salvadori, Nicola, Chipi, Elena , Laske, Christoph , Janowitz, Daniel , Anastasiou, Anna, Parveen, Kayenat, López‐García, Sara , Antonell, Anna , Belezhanska, Diyana , Solís, Patricia , Medel, Nancy , Lisso, Julieta, Sevillano, Zulma, Politis, Daniel Gustavo , Cores, Valeria, Cuesta, Carolina , Ortíz, Cecilia, Bacha, Juan Ignacio, Rios, Mario, Saenz, Aldo, Abalos, Mariana Sanchez, Köhler, Eduardo, Palacio, Dana Lis, Etchepareborda, Ignacio, Prestia, Federico Ariel, Galeano, Pablo , Castaño, Eduardo M., Germani, Sandra, Toso, Carlos Reyes, Rojo, Matias, Ingino, Carlos A. , Mangone, Carlos A., Engelborghs, Sebastiaan , Nielsen, Sune Fallgaard, Farotti, Lucia , Biessels, Geert Jan , Fiévet, Nathalie, Forsell, Charlotte , Thonberg, Håkan, Bjerke, Maria , Roeck, Ellen De , Olivar, Natividad , Sachdev, Perminder S. , Magda, Tsolaki, Rossi, Giacomina, Andreassen, Ole A., Sims, Rebecca , Aguilera, N., Alarcón, Estefanía Burgos, Buendia, Marie‐Annick , Rojas, Itziar de , Diego, S. , Guitart, M., González-Péerez, A, Lafuente, A., Martin, Elisabeth , Martinez, M.T.M., Marquié, M, Olivé, C. , Pelejà, E., Puerta, R, Sáez, ME, Táarraga, L, Valero, S, Alonso, MD, Amer-Ferrer, G., Antequera, M., Antúnez, Carmen , Bernal, M. , Bullido, MJ, Ja, Burguera, Carrillo, F, Casajeros, MJ, Cruz-Gamero, JM, Escuela, R, Franco, Emilio, García-Alberca, JM, Madrona, S. García, Gómez-Garre, P, Hevilla, S., Espinosa, MA Labrador, Legaz, A. , Lleóo, A, Munáin, A Lóopez de, Marín-Muñoz, Juan, Marín, T, Marquié, M, Martínez, B. , Álvarez, A Martínez-Lage, Iriarte, M Mendioroz, Tur, J Péerez, Ripoll, G. Piñol, Ráabano, A, Asúa, Diego Real de , Rodrigo, S., Royo, JL, Díaz, R. Sanchez del Valle, Sánchez‐Juan, Pascual, Sastre, Isabel , Valero, S, Vicente, MP, Vigo-Ortega, R, Shadrin, Alexey A, Rongve, Arvid, Bosnes, Ingunn , Athanasiu, Lavinia, Aarsland, Dag, Andreassen, Ole A., Epelbaum, Jacques, Wallon, David, Hannequin, Didier , Campion, Dominique , Dermecourt, Vincent, Dubois, Bruno , Amouyel, Phillippe, Sims, Rebecca, Gerrish, Amy, Thomas, Charlene , Meggy, Alun, Davies, Chloe, Dowzell, Kimberley, Bernardo-Harrington, Mateus, Hoffmann, Per, Brown, Kristelle, Schott, Jonathan M., Rossor, Martin, Ryan, Natalie S. , Uphill, James, Al-Chalabi, Ammar, Bass, Nick, Abraham, Richard, Kölsch, Heike, Schürmann, Britta, Lacour, ndré, Herold, Christine, Johnston, Janet, Todd, Stephen, Proitsi, Petra, Patel, Yogen, Warden, Donald, Wilcock, Gordon , Clarke, Robert , Lawlor, Brian, McQuillin, Andrew, Hardy, John, Brayne, Carol, Deloukas, Panagiotis, Sussams, Rebecca, Warner, Nick, Bayer, Anthony, Singleton, Andrew, Rujescu, Dan, Giegling, Ina, Klopp, Norman, Mayhaus, Manuel, Riemenschneider, Matthias, Pinchler, Sabrina, Feulner, Thomas, Bussche, Hendrik den, Scherer, Martin, Hüll, Michael, Frölich, Lutz, Wichmann, H‐Erich, Jöckel, Karl‐Heinz , Moebus, Susanne, Kauwe, John, Mayo, Kevin H. , Escott-Price, Valentina, Peng, Rong , Tan, Louis, Tandiono, Moses , Ng, Ebonne, Prakash, Kumar‐M., Au, Wing‐Lok , Meah, Wee-Yang, Mok, Shi Qi, Chan, Anne , Chen, Ling , Jeon, Beom S., Lin, Juei‐Jueng , Pei, Zhong , Shi, Changhe , Song, Kyuyoung, Wu, Yih‐Ru , Xu, Yuming , Yan, Yaping , Yang, Jing , Zhang, Bao Rong, Le Guen, Yann , Damotte, Vincent , During, Emmanuel , Hort, Jakub , Lin, Ling , Niida, Shumpei , Pasquier, Florence , Real, Luis M , Rujescu, Dan , Spalletta, Gianfranco , Zetterberg, Henrik , Andreassen, Ole A , Tsolaki, Magda , Foo, Jia Nee , Mignot, Emmanuel , Dichgans, Martin , Ramirez, Alfredo , Ross, Owen A , Sachdev, Perminder S , Hardy, John , Nicolas, Gaël , Alvarez, Victoria , Mir, Pablo , Pastor, Pau , Boada, Merce , García-González, Pablo , Molina-Porcel, Laura , de Mendonça, Alexandre , Graff, Caroline , Ambati, Aditya , Yu, Eric , Rojas, Itziar de, Leal, Thiago Peixoto , Miyashita, Akinori , Küçükali, Fahri , Belloy, Michaël E. , Benussi, Luisa , Borroni, Barbara , Bullido, María J. , Caffarra, Paolo , Clarimón, Jordi , Darling, Daniel, Debette, Stéphanie , Deleuze, Jean‐François , Galimberti, Daniela , García-González, Pablo, Goldhardt, Oliver , Hanon, Olivier , Heilmann‐Heimbach, Stefanie , Holstege, Henne H. , Hort, Jakub , Mecocci, Patrizia , Moebus, Susanne , Nacmias, Benedetta , Parnetti, Lucilla , Pasquier, Florence , Pijnenburg, Yolande A.L. , Piñol‐Ripoll, Gerard , Rainero, Innocenzo , Royo, José Luís , Scheltens, Philip , Scherbaum, Norbert , Seripa, Davide , Skoog, Ingmar , Squassina, Alessio , Swieten, John C. van , Sánchez‐Valle, Raquel , Teunissen, Charlotte E. , Vyhnálek, Martin , Wærn, Margda , Wiltfang, Jens , Zhang, Jing , EADB, group, GR@ACE study, DemGene, EADI, GERAD, Zetterberg, Henrik , Williams, Julie , Amouyel, Philippe , Tsolaki, Magda , Frikke-Schmidt, Ruth , Sleegers, Kristel , Toda, Tatsushi , Ingelsson, Martin , Rossi, Giacomina, Hiltunen, Mikko O. , Ozaki, Kouichi , Sims, Rebecca, Foo, Jia Nee , Flier, Wiesje M. van der , Ikeuchi, Takeshi , Mata, Ignácio F. , Ruiz, Agustı́n , Gan‐Or, Ziv , Andrade, Víctor , Amin, Najaf , Campos-Martín, Rafael , Holmans, Peter , Kleineidam, Luca , Lee, Sven J. van der , Rojas, Itziar de, Yaqub, Amber , Prokic, Ivana, Costa, Marcos R. , Chapuis, Julien , Ahmad, Shahzad , Aarsland, Dag, Alarcón‐Martín, Emilio , Alcolea, Daniel , Alegret, Montserrat , Álvarez, Ignacio , Appollonio, Ildebrando Marco , Arcaro, Marina , Athanasiu, Lavinia, Berr, Claudine , Bessi, Valentina , Binetti, Giuliano , Boschi, Silvia , Bråthen, Geir , Bresner, Catherine , Brodaty, Henry , Brookes, Keeley J. , Burholt, Vanessa, Calero, Miguel , Chêne, Geneviève , Carracedo, Ãngel , Cervera‐Carles, Laura , Charbonnier, Camille , Claassen, Jurgen A.H.R. , Conti, Elisa , Corma‐Gómez, Anaïs , Custodero, Carlo , Dalmasso, Carolina , Dardiotis, Efthimios , Deyn, Peter Paul De , Ser, Teodoro del , Denning, Nicola , Diehl‐Schmid, Janine , Díez-Fairén, Mónica , Rossi, Paolo Dionigi , Djurovic, Srdjan , Duron, Emmanuelle , Escott-Price, Valentina, Espinosa, Ana , Ferri, Evelyn , Fischer, Peter A. , Fladby, Tormod , Fortea, Juan , Fostinelli, Silvia , Fox, Nick C. , Frank, Ana , Froelich, Lutz , García-González, Pablo, Ghidoni, Roberta , Giegling, Ina, Grimmer, Timo , Guetta‐Baranes, Tamar , Haapasalo, Annakaisa , Hadjigeorgiou, Georgios M. , Hampel, Harald , Hardy, John, Heneka, Michael T. , Hernández, Isabel, Herrmann, Martin J. , Hoffmann, Per, Holmes, Clive , Kivipelto, Miia , Kornhuber, Johannes , Kosmidis, Mary H. , Laukka, Erika J. , Lauria, Alessandra , Lehtisalo, Jenni , Lleó, Alberto , Munain, Adolfo Lopez de, Macías, Juan, MacLeod, Catherine Anne , Mangialasche, Francesca , Marquié, Marta , Marshall, Iain James , Mead, Simon , Medina, Miguel , Meggy, Alun, Menéndez‐González, Manuel , Moebus, Susanne, Mol, Merel O. , Montrreal, Laura , Morgan, Kevin , Ngandu, Tiia , Olaso, Robert , Orellana, Adelina , Ortega, Gemma , Padovani, Alessandro , Pérez‐Cordón, Alba , Pineda, Juan Antonio , Piñol-Ripoll, Gerard, Pisanu, Claudia , Posthuma, Daniëlle , Priller, Josef , Quintela, Inés , Reinders, Marcel J. 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Proceedings of the National Academy of Sciences | August 29, 2023 | Volume: 120 | Issue: 36 | Pages: No page available

10.1073/pnas.2302720120 | PMID 37643212

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.

Citations

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

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers