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

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 Parveen; Takashi 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; Caroline Graff; Edna Grünblatt; Olivier Hanon; Lucrezia Hausner; Inez Ramakers; Frans Verhey; Asian Parkinson’s Disease Genetics consortium; DEGESCO consortium; DemGene; EADB; EADI; GERAD; GR@ACE study group

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

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 Parveen, Takashi Morizono, Hyeonseul Park, Benjamin Grenier-Boley, Tatsuhiko Naito, Fahri Küçükali, Seth D. Talyansky, Selina Maria YogeshwarVicente 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, Caroline Graff, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Inez Ramakers, Frans Verhey, Asian Parkinson’s Disease Genetics consortium, DEGESCO consortium, DemGene, EADB, EADI, GERAD, GR@ACE study group

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 Aß42. 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 language	English
Article number	e2302720120
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	120
Issue number	36
DOIs	https://doi.org/10.1073/pnas.2302720120
Publication status	Published - 5 Sept 2023

Keywords

Alzheimer’s dementia
autoimmunity
HLA
neurodegeneration
Parkinson’s disease

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10.1073/pnas.2302720120Licence: CC BY

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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., ... GR@ACE study group (2023). 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. Proceedings of the National Academy of Sciences of the United States of America, 120(36), Article e2302720120. https://doi.org/10.1073/pnas.2302720120

@article{0279f8d348154343b2a88c695ed7e72e,

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",

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 A{\ss}42. 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 = "Alzheimer{\textquoteright}s dementia, autoimmunity, HLA, neurodegeneration, Parkinson{\textquoteright}s disease",

author = "{Le Guen}, Yann and Guo Luo and Aditya Ambati and Vincent Damotte and Iris Jansen and Eric Yu and Aude Nicolas and {de Rojas}, Itziar and {Peixoto Leal}, Thiago and Akinori Miyashita and C{\'e}line Bellenguez and Lian, {Michelle Mulan} and Kayenat Parveen and Takashi Morizono and Hyeonseul Park and Benjamin Grenier-Boley and Tatsuhiko Naito and Fahri K{\"u}{\c c}{\"u}kali and Talyansky, {Seth D.} and Yogeshwar, {Selina Maria} and Vicente Sempere and Wataru Satake and Victoria Alvarez and Beatrice Arosio and Belloy, {Michael E.} and Luisa Benussi and Anne Boland and Barbara Borroni and Bullido, {Mar{\'i}a J.} and Paolo Caffarra and Jordi Clarimon and Antonio Daniele and Daniel Darling and St{\'e}phanie Debette and Deleuze, {Jean Fran{\c c}ois} and Martin Dichgans and Carole Dufouil and Emmanuel During and Emrah D{\"u}zel and Daniela Galimberti and Guillermo Garcia-Ribas and Garc{\'i}a-Alberca, {Jos{\'e} Mar{\'i}a} and Pablo Garc{\'i}a-Gonz{\'a}lez and Vilmantas Giedraitis and Oliver Goldhardt and Caroline Graff and Edna Gr{\"u}nblatt and Olivier Hanon and Lucrezia Hausner and Inez Ramakers and Frans Verhey and {Asian Parkinson{\textquoteright}s Disease Genetics consortium} and {DEGESCO consortium} and DemGene and EADB and EADI and GERAD and {GR@ACE study group}",

year = "2023",

month = sep,

day = "5",

doi = "10.1073/pnas.2302720120",

language = "English",

volume = "120",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "36",

}

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, MM, Parveen, K, Morizono, T, Park, H, Grenier-Boley, B, Naito, T, Küçükali, F, Talyansky, SD, Yogeshwar, SM, Sempere, V, Satake, W, Alvarez, V, Arosio, B, Belloy, ME, Benussi, L, Boland, A, Borroni, B, Bullido, MJ, Caffarra, P, Clarimon, J, Daniele, A, Darling, D, Debette, S, Deleuze, JF, Dichgans, M, Dufouil, C, During, E, Düzel, E, Galimberti, D, Garcia-Ribas, G, García-Alberca, JM, García-González, P, Giedraitis, V, Goldhardt, O, Graff, C, Grünblatt, E, Hanon, O, Hausner, L, Ramakers, I , Verhey, F, Asian Parkinson’s Disease Genetics consortium, DEGESCO consortium, DemGene, EADB, EADI, GERAD & GR@ACE study group 2023, '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', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 36, e2302720120. https://doi.org/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. / Le Guen, Yann; Luo, Guo; Ambati, Aditya et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 120, No. 36, e2302720120, 05.09.2023.

Research output: Contribution to journal › Article › Academic › peer-review

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 - Hanon, Olivier

AU - Hausner, Lucrezia

AU - Ramakers, Inez

AU - Verhey, Frans

AU - Asian Parkinson’s Disease Genetics consortium

AU - DEGESCO consortium

AU - DemGene

AU - EADB

AU - EADI

AU - GERAD

AU - GR@ACE study group

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 Aß42. 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 Aß42. 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 - autoimmunity

KW - HLA

KW - neurodegeneration

KW - Parkinson’s disease

U2 - 10.1073/pnas.2302720120

DO - 10.1073/pnas.2302720120

M3 - Article

SN - 0027-8424

VL - 120

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 -

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

Abstract

Keywords

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