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.

Details

Ressource 1Download: 37643212_BIB_017FA8B8CC9B.pdf (2781.41 [Ko])
State: Public
Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_017FA8B8CC9B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
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.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Le Guen Y., Luo G., Ambati A., Damotte V., Jansen I., Yu E., Nicolas A., de Rojas I., Peixoto Leal T., Miyashita A., Bellenguez C., Lian M.M., Parveen K., Morizono T., Park H., Grenier-Boley B., Naito T., Küçükali F., Talyansky S.D., Yogeshwar S.M., Sempere V., Satake W., Alvarez V., Arosio B., Belloy M.E., Benussi L., Boland A., Borroni B., Bullido M.J., Caffarra P., Clarimon J., Daniele A., Darling D., Debette S., Deleuze J.F., Dichgans M., Dufouil C., During E., Düzel E., Galimberti D., Garcia-Ribas G., García-Alberca J.M., García-González P., Giedraitis V., Goldhardt O., Graff C., Grünblatt E., Hanon O., Hausner L., Heilmann-Heimbach S., Holstege H., Hort J., Jung Y.J., Jürgen D., Kern S., Kuulasmaa T., Lee K.H., Lin L., Masullo C., Mecocci P., Mehrabian S., de Mendonça A., Boada M., Mir P., Moebus S., Moreno F., Nacmias B., Nicolas G., Niida S., Nordestgaard B.G., Papenberg G., Papma J., Parnetti L., Pasquier F., Pastor P., Peters O., Pijnenburg YAL, Piñol-Ripoll G., Popp J., Porcel L.M., Puerta R., Pérez-Tur J., Rainero I., Ramakers I., Real L.M., Riedel-Heller S., Rodriguez-Rodriguez E., Ross O.A., Royo L.J., Rujescu D., Scarmeas N., Scheltens P., Scherbaum N., Schneider A., Seripa D., Skoog I., Solfrizzi V., Spalletta G., Squassina A., van Swieten J., Sánchez-Valle R., Tan E.K., Tegos T., Teunissen C., Thomassen J.Q., Tremolizzo L., Vyhnalek M., Verhey F., Waern M., Wiltfang J., Zhang J., Zetterberg H., Blennow K., He Z., Williams J., Amouyel P., Jessen F., Kehoe P.G., Andreassen O.A., Van Duin C., Tsolaki M., Sánchez-Juan P., Frikke-Schmidt R., Sleegers K., Toda T., Zettergren A., Ingelsson M., Okada Y., Rossi G., Hiltunen M., Gim J., Ozaki K., Sims R., Foo J.N., van der Flier W., Ikeuchi T., Ramirez A., Mata I., Ruiz A., Gan-Or Z., Lambert J.C., Greicius M.D., Mignot E.
Working group(s)
EADB, GR@ACE study group, DEGESCO consortium, DemGene, EADI, GERAD, Asian Parkinson's Disease Genetics consortium
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
05/09/2023
Peer-reviewed
Oui
Volume
120
Number
36
Pages
e2302720120
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Humans, Alzheimer Disease/genetics, Histocompatibility Antigens, HLA Antigens, HLA-DRB1 Chains/genetics, Parkinson Disease/genetics, Alzheimer’s dementia, HLA, Parkinson’s disease, autoimmunity, neurodegeneration
Pubmed
Web of science
Open Access
Yes
Create date
19/09/2023 15:21
Last modification date
08/08/2024 7:29
Usage data