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, 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.

doi:10.1073/pnas.2302720120

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

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Version: Final published version
License: CC BY 4.0

Serval ID

serval:BIB_017FA8B8CC9B

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

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

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

URN

urn:nbn:ch:serval-BIB_017FA8B8CC9B6

OAI-PMH

oai:serval.unil.ch:BIB_017FA8B8CC9B

DOI

10.1073/pnas.2302720120

Pubmed

37643212

Web of science

001119291700001

Open Access

Yes