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

European Alzheimer & Dementia BioBank (EADB); The GR@ACE study group; DEGESCO consortium; Demgene; the European AD Initiative (EADI); GERAD; Asian Parkinson’s Disease Genetics consortium; 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; Henne Holstege; Janne Papma; John van Swieten; Jing Zhang; Kristel Sleegers

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-DRB104* subtypes

European Alzheimer & Dementia BioBank (EADB), The GR@ACE study group, DEGESCO consortium, Demgene, the European AD Initiative (EADI), GERAD, Asian Parkinson’s Disease Genetics consortium, 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 ParveenTakashi 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, Henne Holstege, Janne Papma, John van Swieten, Jing Zhang, Kristel Sleegers

Neurology

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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.

Original language	English
Article number	e2302720120
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 - 29 Aug 2023

Bibliographical note

Funding Information:
for AD Consortium (GERAD), the European AD Initiative (EADI), the Norwegian DemGene (DemGene), the Bonn study (Bonn), the Copenhagen City Heart Study (CCHS), the AD Genetics Consortium (ADGC), the Alzheimer Disease Sequencing Project (ADSP), the UK Biobank, the Gwangju Alzheimer’s and Related Dementias (GARD) study, the Japanese Genetic Study Consortium for AD from Niigata University and National Center for Geriatrics and Gerontology (NCGG). The PD samples included in the HLA fine-mapping analysis are part of the following datasets for which the phenotyping, genotyping, and quality control have been described elsewhere (8, 16, 17, 22, 25, 72): International PD Genomics Consortium (IPDGC) NeuroX dataset, McGill University (McGill), National Institute of Neurological Disorders and Stroke (NINDS) Genome-Wide genotyping in PD, NeuroGenetics Research Consortium (NGRC), Oslo PD Study (Oslo), Parkinson’s Progression Markers Initiative (PPMI), Autopsy-Confirmed Parkinson Disease GWAS Consortium (APDGC), the UK Biobank, East Asians samples from Japan, China, Singapore, Taiwan, and Hong-Kong (EastAsians-PD), 23andMe, and the Latin American Research Consortium on the Genetics of PD (LARGE-PD).

Funding Information:
ACKNOWLEDGMENTS. This work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer’s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (#2018-02532, H.Z.), the European Research Council (#681712, H.Z.), and the Swedish State Support for Clinical Research (#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendix.

Publisher Copyright:
Copyright © 2023 the Author(s).

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European Alzheimer & Dementia BioBank (EADB), The GR@ACE study group, DEGESCO consortium, Demgene, the European AD Initiative (EADI), GERAD, Asian Parkinson’s Disease Genetics consortium, 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., ... Sleegers, K. (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{29e7c51a3228483f9aad7785369d3f0a,

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 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.",

author = "\{European Alzheimer \& Dementia BioBank (EADB)\} and \{The GR@ACE study group\} and \{DEGESCO consortium\} and Demgene and \{the European AD Initiative (EADI)\} and GERAD and \{Asian Parkinson{\textquoteright}s Disease Genetics consortium\} and \{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 Henne Holstege and Janne Papma and \{van Swieten\}, John and Jing Zhang and Kristel Sleegers",

note = "Funding Information: for AD Consortium (GERAD), the European AD Initiative (EADI), the Norwegian DemGene (DemGene), the Bonn study (Bonn), the Copenhagen City Heart Study (CCHS), the AD Genetics Consortium (ADGC), the Alzheimer Disease Sequencing Project (ADSP), the UK Biobank, the Gwangju Alzheimer{\textquoteright}s and Related Dementias (GARD) study, the Japanese Genetic Study Consortium for AD from Niigata University and National Center for Geriatrics and Gerontology (NCGG). The PD samples included in the HLA fine-mapping analysis are part of the following datasets for which the phenotyping, genotyping, and quality control have been described elsewhere (8, 16, 17, 22, 25, 72): International PD Genomics Consortium (IPDGC) NeuroX dataset, McGill University (McGill), National Institute of Neurological Disorders and Stroke (NINDS) Genome-Wide genotyping in PD, NeuroGenetics Research Consortium (NGRC), Oslo PD Study (Oslo), Parkinson{\textquoteright}s Progression Markers Initiative (PPMI), Autopsy-Confirmed Parkinson Disease GWAS Consortium (APDGC), the UK Biobank, East Asians samples from Japan, China, Singapore, Taiwan, and Hong-Kong (EastAsians-PD), 23andMe, and the Latin American Research Consortium on the Genetics of PD (LARGE-PD). Funding Information: ACKNOWLEDGMENTS. This work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer{\textquoteright}s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (\#2018-02532, H.Z.), the European Research Council (\#681712, H.Z.), and the Swedish State Support for Clinical Research (\#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille M{\'e}tropole Communaut{\'e} Urbaine, and the French government{\textquoteright}s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendix. Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s).",

year = "2023",

month = aug,

day = "29",

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",

}

European Alzheimer & Dementia BioBank (EADB), The GR@ACE study group, DEGESCO consortium, Demgene, the European AD Initiative (EADI), GERAD, Asian Parkinson’s Disease Genetics consortium, 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, Holstege, H, Papma, J , van Swieten, J, Zhang, J & Sleegers, K 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. / European Alzheimer & Dementia BioBank (EADB); The GR@ACE study group; DEGESCO consortium et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 120, No. 36, e2302720120, 29.08.2023.

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 - European Alzheimer & Dementia BioBank (EADB)

AU - The GR@ACE study group

AU - DEGESCO consortium

AU - Demgene

AU - the European AD Initiative (EADI)

AU - GERAD

AU - Asian Parkinson’s Disease Genetics consortium

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 - Holstege, Henne

AU - Papma, Janne

AU - van Swieten, John

AU - Zhang, Jing

AU - Sleegers, Kristel

N1 - Funding Information: for AD Consortium (GERAD), the European AD Initiative (EADI), the Norwegian DemGene (DemGene), the Bonn study (Bonn), the Copenhagen City Heart Study (CCHS), the AD Genetics Consortium (ADGC), the Alzheimer Disease Sequencing Project (ADSP), the UK Biobank, the Gwangju Alzheimer’s and Related Dementias (GARD) study, the Japanese Genetic Study Consortium for AD from Niigata University and National Center for Geriatrics and Gerontology (NCGG). The PD samples included in the HLA fine-mapping analysis are part of the following datasets for which the phenotyping, genotyping, and quality control have been described elsewhere (8, 16, 17, 22, 25, 72): International PD Genomics Consortium (IPDGC) NeuroX dataset, McGill University (McGill), National Institute of Neurological Disorders and Stroke (NINDS) Genome-Wide genotyping in PD, NeuroGenetics Research Consortium (NGRC), Oslo PD Study (Oslo), Parkinson’s Progression Markers Initiative (PPMI), Autopsy-Confirmed Parkinson Disease GWAS Consortium (APDGC), the UK Biobank, East Asians samples from Japan, China, Singapore, Taiwan, and Hong-Kong (EastAsians-PD), 23andMe, and the Latin American Research Consortium on the Genetics of PD (LARGE-PD). Funding Information: ACKNOWLEDGMENTS. This work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer’s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (#2018-02532, H.Z.), the European Research Council (#681712, H.Z.), and the Swedish State Support for Clinical Research (#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendix. Publisher Copyright: Copyright © 2023 the Author(s).

PY - 2023/8/29

Y1 - 2023/8/29

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.

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U2 - 10.1073/pnas.2302720120

DO - 10.1073/pnas.2302720120

M3 - Article

C2 - 37643212

AN - SCOPUS:85168987916

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 -

European Alzheimer & Dementia BioBank (EADB), The GR@ACE study group, DEGESCO consortium, Demgene, the European AD Initiative (EADI), GERAD et al. 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. 2023 Aug 29;120(36):e2302720120. doi: 10.1073/pnas.2302720120