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, Itziar de Rojas, 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, Pablo García-González, 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
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.