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

EADB, The GR@ACE study group, DEGESCO consortium, Demgene, EADI, GERAD, Asian Parkinson’s Disease Genetics consortium, Yann Le Guen, Guo Luo, Aditya Ambati, Vincent Damotte, Iris Jansen, Eric Yu, Aude Nicolas, Itziar de Rojas, Thiago Peixoto Leal, Akinori Miyashita, Céline Bellenguez, Michelle Mulan Lian, Kayenat ParveenTakashi Morizono, Hyeonseul Park, Benjamin Grenier-Boley, Tatsuhiko Naito, Fahri Küçükali, Seth D. Talyansky, Selina Maria Yogeshwar, Vicente Sempere, Wataru Satake, Victoria Alvarez, Beatrice Arosio, Michael E. Belloy, Luisa Benussi, Anne Boland, Barbara Borroni, María J. Bullido, Paolo Caffarra, Jordi Clarimon, Antonio Daniele, Daniel Darling, Stéphanie Debette, Jean François Deleuze, Martin Dichgans, Carole Dufouil, Emmanuel During, Emrah Düzel, Daniela Galimberti, Guillermo Garcia-Ribas, José María García-Alberca, Pablo García-González, Vilmantas Giedraitis, Oliver Goldhardt, Henne Holstege, Janne Papma, John van Swieten, Jing Zhang, Kristel Sleegers

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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.

Original languageEnglish
Article numbere2302720120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
Publication statusPublished - 29 Aug 2023

Bibliographical note

Funding Information:
for AD Consortium (GERAD), the European AD Initiative (EADI), the Norwegian DemGene (DemGene), the Bonn study (Bonn), the Copenhagen City Heart Study (CCHS), the AD Genetics Consortium (ADGC), the Alzheimer Disease Sequencing Project (ADSP), the UK Biobank, the Gwangju Alzheimer’s and Related Dementias (GARD) study, the Japanese Genetic Study Consortium for AD from Niigata University and National Center for Geriatrics and Gerontology (NCGG). The PD samples included in the HLA fine-mapping analysis are part of the following datasets for which the phenotyping, genotyping, and quality control have been described elsewhere (8, 16, 17, 22, 25, 72): International PD Genomics Consortium (IPDGC) NeuroX dataset, McGill University (McGill), National Institute of Neurological Disorders and Stroke (NINDS) Genome-Wide genotyping in PD, NeuroGenetics Research Consortium (NGRC), Oslo PD Study (Oslo), Parkinson’s Progression Markers Initiative (PPMI), Autopsy-Confirmed Parkinson Disease GWAS Consortium (APDGC), the UK Biobank, East Asians samples from Japan, China, Singapore, Taiwan, and Hong-Kong (EastAsians-PD), 23andMe, and the Latin American Research Consortium on the Genetics of PD (LARGE-PD).

Funding Information:
ACKNOWLEDGMENTS. This work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer’s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (#2018-02532, H.Z.), the European Research Council (#681712, H.Z.), and the Swedish State Support for Clinical Research (#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendix.

Publisher Copyright:
Copyright © 2023 the Author(s).


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