TY - JOUR
T1 - 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
AU - Le Guen, Yann
AU - Luo, Guo
AU - Ambati, Aditya
AU - Damotte, Vincent
AU - Jansen, Iris
AU - Yu, Eric
AU - Nicolas, Aude
AU - de Rojas, Itziar
AU - Peixoto Leal, Thiago
AU - Miyashita, Akinori
AU - Bellenguez, Céline
AU - Lian, Michelle Mulan
AU - Parveen, Kayenat
AU - Morizono, Takashi
AU - Park, Hyeonseul
AU - Grenier-Boley, Benjamin
AU - Naito, Tatsuhiko
AU - Küçükali, Fahri
AU - Talyansky, Seth D
AU - Yogeshwar, Selina Maria
AU - Sempere, Vicente
AU - Satake, Wataru
AU - Alvarez, Victoria
AU - Arosio, Beatrice
AU - Belloy, Michael E
AU - Benussi, Luisa
AU - Boland, Anne
AU - Borroni, Barbara
AU - Bullido, María J
AU - Caffarra, Paolo
AU - Clarimon, Jordi
AU - Daniele, Antonio
AU - Darling, Daniel
AU - Debette, Stéphanie
AU - Deleuze, Jean-François
AU - Dichgans, Martin
AU - Dufouil, Carole
AU - During, Emmanuel
AU - Düzel, Emrah
AU - Galimberti, Daniela
AU - Garcia-Ribas, Guillermo
AU - García-Alberca, José María
AU - García-González, Pablo
AU - Giedraitis, Vilmantas
AU - Goldhardt, Oliver
AU - Graff, Caroline
AU - Grünblatt, Edna
AU - Nordestgaard, Børge G
AU - Thomassen, Jesper Qvist
AU - Frikke-Schmidt, Ruth
AU - EADB
PY - 2023/9/5
Y1 - 2023/9/5
N2 - 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.
AB - 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.
KW - Alzheimer’s dementia
KW - HLA
KW - Parkinson’s disease
KW - autoimmunity
KW - neurodegeneration
UR - https://www.scopus.com/pages/publications/85168987916
U2 - 10.1073/pnas.2302720120
DO - 10.1073/pnas.2302720120
M3 - Journal article
C2 - 37643212
SN - 0027-8424
VL - 120
SP - e2302720120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 36
M1 - e2302720120
ER -