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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 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.
Affiliation
  • Le Guen Y; Department of Neurology and Neurological Sciences, Stanford University, Stanford 94305, CA.
  • Luo G; Institut du Cerveau-Paris Brain Institute-ICM, Paris 75013, France.
  • Ambati A; Center for Sleep Sciences and Medicine, Stanford University, Palo Alto 94304, CA.
  • Damotte V; Center for Sleep Sciences and Medicine, Stanford University, Palo Alto 94304, CA.
  • Jansen I; Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liés au vieillissement, Lille 59000, France.
  • Yu E; Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands.
  • Nicolas A; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije University, 1081 HV Amsterdam, The Netherlands.
  • de Rojas I; The Neuro (Montreal Neurological Institute-Hospital), Montreal, Quebec H3A 2B4, Canada.
  • Peixoto Leal T; Department of Human Genetics, McGill University, Montreal, Quebec H3A 0G4, Canada.
  • Miyashita A; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.
  • Bellenguez C; Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liés au vieillissement, Lille 59000, France.
  • Lian MM; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona 08029, Spain.
  • Parveen K; Networking Research Center on Neurodegenerative Diseases (CIRNED), Instituto de Salud Carlos III, Madrid 28029, Spain.
  • Morizono T; Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland 44196, OH.
  • Park H; Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 950-218, Japan.
  • Grenier-Boley B; Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liés au vieillissement, Lille 59000, France.
  • Naito T; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore.
  • Küçükali F; Laboratory of Neurogenetics, Genome Institute of Singapore, A*STAR, Singapore 138672, Singapore.
  • Talyansky SD; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany.
  • Yogeshwar SM; Department of Neurodegenerative diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn 53127, Germany.
  • Sempere V; Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan.
  • Satake W; Department of Biomedical Science, Chosun University, Gwangju 61452, Korea.
  • Alvarez V; Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liés au vieillissement, Lille 59000, France.
  • Arosio B; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
  • Belloy ME; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 192-0982, Japan.
  • Benussi L; Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp 2610, Belgium.
  • Boland A; Laboratory of Neurogenetics, Institute Born-Bunge, Antwerp 2610, Belgium.
  • Borroni B; Department of Biomedical Sciences, University of Antwerp, Antwerp 2000, Belgium.
  • Bullido MJ; Department of Neurology and Neurological Sciences, Stanford University, Stanford 94305, CA.
  • Caffarra P; Center for Sleep Sciences and Medicine, Stanford University, Palo Alto 94304, CA.
  • Clarimon J; Department of Neurology, Charité-Universitätsmedizin, Berlin 10117, Germany.
  • Daniele A; Charité-Universitätsmedizin Berlin, Einstein Center for Neurosciences Berlin, Berlin 10117, Germany.
  • Darling D; Center for Sleep Sciences and Medicine, Stanford University, Palo Alto 94304, CA.
  • Debette S; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 192-0982, Japan.
  • Deleuze JF; Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo 33011, Spain.
  • Dichgans M; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo 33011, Spain.
  • Dufouil C; Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy.
  • During E; Department of Neurology and Neurological Sciences, Stanford University, Stanford 94305, CA.
  • Düzel E; Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy.
  • Galimberti D; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry 91057, France.
  • Garcia-Ribas G; Department of Clinical and Experimental Sciences, Centre for Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia 25123, Italy.
  • García-Alberca JM; Networking Research Center on Neurodegenerative Diseases (CIRNED), Instituto de Salud Carlos III, Madrid 28029, Spain.
  • García-González P; Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Universidad Autónoma de Madrid, Madrid 28049, Spain.
  • Giedraitis V; Instituto de Investigacion Sanitaria "Hospital la Paz" (IdIPaz), Madrid 48903, Spain.
  • Goldhardt O; Unit of Neurology, University of Parma and AOU, Parma 43121, Italy.
  • Graff C; Networking Research Center on Neurodegenerative Diseases (CIRNED), Instituto de Salud Carlos III, Madrid 28029, Spain.
  • Grünblatt E; Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona 08193, Spain.
  • Hanon O; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome 00168, Italy.
  • Hausner L; Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome 00168, Italy.
  • Heilmann-Heimbach S; Center for Sleep Sciences and Medicine, Stanford University, Palo Alto 94304, CA.
Proc Natl Acad Sci U S A ; 120(36): e2302720120, 2023 09 05.
Article in En | MEDLINE | ID: mdl-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 Aß42. 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.
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Full text: 1 Database: MEDLINE Main subject: Parkinson Disease / Alzheimer Disease / HLA-DRB1 Chains Limits: Humans Language: En Year: 2023 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Parkinson Disease / Alzheimer Disease / HLA-DRB1 Chains Limits: Humans Language: En Year: 2023 Type: Article