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 - EADB
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 - Kehoe, Patrick G
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 - Humans
KW - Alzheimer Disease/genetics
KW - Histocompatibility Antigens
KW - HLA Antigens
KW - HLA-DRB1 Chains/genetics
KW - Parkinson Disease/genetics
U2 - 10.1073/pnas.2302720120
DO - 10.1073/pnas.2302720120
M3 - Article (Academic Journal)
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
ER -
