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

EADB; GR at ACE study group; DEGESCO consortium; Demgene; 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; Caroline Graff; Edna Grünblatt; Olivier Hanon; Lucrezia Hausner; Stefanie Heilmann-Heimbach; Henne Holstege; Jakub Hort; Yoo Jin Jung; Deckert Jürgen; Silke Kern; Teemu Kuulasmaa; Kun Ho Lee; Ling Lin; Carlo Masullo; Patrizia Mecocci; Shima Mehrabian; Alexandre de Mendonça; Mercè Boada; Pablo Mir; Susanne Moebus; Fermin Moreno; Benedetta Nacmias; Gael Nicolas; Shumpei Niida; Børge G. Nordestgaard; Goran Papenberg; Janne Papma; Lucilla Parnetti; Florence Pasquier; Pau Pastor; Oliver Peters; Yolande A.L. Pijnenburg; Gerard Piñol-Ripoll; Julius Popp; Laura Molina Porcel; Raquel Puerta; Jordi Pérez-Tur; Innocenzo Rainero; Inez Ramakers; Luis M. Real; Steffi Riedel-Heller; Eloy Rodriguez-Rodriguez; Owen A. Ross; Jose Luís Royo; Dan Rujescu; Nikolaos Scarmeas; Philip Scheltens; Norbert Scherbaum; Anja Schneider; Davide Seripa; Ingmar Skoog; Vincenzo Solfrizzi; Gianfranco Spalletta; Alessio Squassina; John van Swieten; Raquel Sánchez-Valle; Eng King Tan; Thomas Tegos; Charlotte Teunissen; Jesper Qvist Thomassen; Lucio Tremolizzo; Martin Vyhnalek; Frans Verhey; Margda Waern; Jens Wiltfang; Jing Zhang; Henrik Zetterberg; Kaj Blennow; Zihuai He; Julie Williams; Philippe Amouyel; Frank Jessen; Patrick G. Kehoe; Ole A. Andreassen; Cornelia Van Duin; Magda Tsolaki; Pascual Sánchez-Juan; Ruth Frikke-Schmidt; Kristel Sleegers; Tatsushi Toda; Anna Zettergren; Martin Ingelsson; Yukinori Okada; Giacomina Rossi; Mikko Hiltunen; Jungsoo Gim; Kouichi Ozaki; Rebecca Sims; Jia Nee Foo; Wiesje van der Flier; Takeshi Ikeuchi; Alfredo Ramirez; Ignacio Mata; Agustín Ruiz; Ziv Gan-Or; Jean Charles Lambert; Michael D. Greicius; Emmanuel Mignot

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

EADB, GR at ACE study group, DEGESCO consortium, Demgene, 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, Caroline Graff, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Henne Holstege, Jakub Hort, Yoo Jin Jung, Deckert Jürgen, Silke Kern, Teemu Kuulasmaa, Kun Ho Lee, Ling Lin, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Alexandre de Mendonça, Mercè Boada, Pablo Mir, Susanne Moebus, Fermin Moreno, Benedetta Nacmias, Gael Nicolas, Shumpei Niida, Børge G. Nordestgaard, Goran Papenberg, Janne Papma, Lucilla Parnetti, Florence Pasquier, Pau Pastor, Oliver Peters, Yolande A.L. Pijnenburg, Gerard Piñol-Ripoll, Julius Popp, Laura Molina Porcel, Raquel Puerta, Jordi Pérez-Tur, Innocenzo Rainero, Inez Ramakers, Luis M. Real, Steffi Riedel-Heller, Eloy Rodriguez-Rodriguez, Owen A. Ross, Jose Luís Royo, Dan Rujescu, Nikolaos Scarmeas, Philip Scheltens, Norbert Scherbaum, Anja Schneider, Davide Seripa, Ingmar Skoog, Vincenzo Solfrizzi, Gianfranco Spalletta, Alessio Squassina, John van Swieten, Raquel Sánchez-Valle, Eng King Tan, Thomas Tegos, Charlotte Teunissen, Jesper Qvist Thomassen, Lucio Tremolizzo, Martin Vyhnalek, Frans Verhey, Margda Waern, Jens Wiltfang, Jing Zhang, Henrik Zetterberg, Kaj Blennow, Zihuai He, Julie Williams, Philippe Amouyel, Frank Jessen, Patrick G. Kehoe, Ole A. Andreassen, Cornelia Van Duin, Magda Tsolaki, Pascual Sánchez-Juan, Ruth Frikke-Schmidt, Kristel Sleegers, Tatsushi Toda, Anna Zettergren, Martin Ingelsson, Yukinori Okada, Giacomina Rossi, Mikko Hiltunen, Jungsoo Gim, Kouichi Ozaki, Rebecca Sims, Jia Nee Foo, Wiesje van der Flier, Takeshi Ikeuchi, Alfredo Ramirez, Ignacio Mata, Agustín Ruiz, Ziv Gan-Or, Jean Charles Lambert, Michael D. Greicius, Emmanuel Mignot

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

11 Scopus citations

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
State	Published - 2023

Keywords

Alzheimer’s dementia
autoimmunity
HLA
neurodegeneration
Parkinson’s disease

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10.1073/pnas.2302720120

Cite this

EADB, GR at ACE study group, DEGESCO consortium, Demgene, 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., Leal, T. P., Miyashita, A., Bellenguez, C., Lian, M. M., ... Mignot, E. (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{6acaa98388714de9b56c8212f735f180,

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{\textquoteright}s disease (PD) and Alzheimer{\textquoteright}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 = "Alzheimer{\textquoteright}s dementia, autoimmunity, HLA, neurodegeneration, Parkinson{\textquoteright}s disease",

author = "EADB and {GR at ACE study group} and {DEGESCO consortium} and Demgene and 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 Leal, {Thiago Peixoto} 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 Stefanie Heilmann-Heimbach and Henne Holstege and Jakub Hort and Jung, {Yoo Jin} and Deckert J{\"u}rgen and Silke Kern and Teemu Kuulasmaa and Lee, {Kun Ho} and Ling Lin and Carlo Masullo and Patrizia Mecocci and Shima Mehrabian and {de Mendon{\c c}a}, Alexandre and Merc{\`e} Boada and Pablo Mir and Susanne Moebus and Fermin Moreno and Benedetta Nacmias and Gael Nicolas and Shumpei Niida and Nordestgaard, {B{\o}rge G.} and Goran Papenberg and Janne Papma and Lucilla Parnetti and Florence Pasquier and Pau Pastor and Oliver Peters and Pijnenburg, {Yolande A.L.} and Gerard Pi{\~n}ol-Ripoll and Julius Popp and Porcel, {Laura Molina} and Raquel Puerta and Jordi P{\'e}rez-Tur and Innocenzo Rainero and Inez Ramakers and Real, {Luis M.} and Steffi Riedel-Heller and Eloy Rodriguez-Rodriguez and Ross, {Owen A.} and Royo, {Jose Lu{\'i}s} and Dan Rujescu and Nikolaos Scarmeas and Philip Scheltens and Norbert Scherbaum and Anja Schneider and Davide Seripa and Ingmar Skoog and Vincenzo Solfrizzi and Gianfranco Spalletta and Alessio Squassina and {van Swieten}, John and Raquel S{\'a}nchez-Valle and Tan, {Eng King} and Thomas Tegos and Charlotte Teunissen and Thomassen, {Jesper Qvist} and Lucio Tremolizzo and Martin Vyhnalek and Frans Verhey and Margda Waern and Jens Wiltfang and Jing Zhang and Henrik Zetterberg and Kaj Blennow and Zihuai He and Julie Williams and Philippe Amouyel and Frank Jessen and Kehoe, {Patrick G.} and Andreassen, {Ole A.} and {Van Duin}, Cornelia and Magda Tsolaki and Pascual S{\'a}nchez-Juan and Ruth Frikke-Schmidt and Kristel Sleegers and Tatsushi Toda and Anna Zettergren and Martin Ingelsson and Yukinori Okada and Giacomina Rossi and Mikko Hiltunen and Jungsoo Gim and Kouichi Ozaki and Rebecca Sims and Foo, {Jia Nee} and {van der Flier}, Wiesje and Takeshi Ikeuchi and Alfredo Ramirez and Ignacio Mata and Agust{\'i}n Ruiz and Ziv Gan-Or and Lambert, {Jean Charles} and Greicius, {Michael D.} and Emmanuel Mignot",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s).",

year = "2023",

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",

number = "36",

}

EADB, GR at ACE study group, DEGESCO consortium, Demgene, 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, Leal, TP, 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, Heilmann-Heimbach, S, Holstege, H, Hort, J, Jung, YJ, Jürgen, D, Kern, S, Kuulasmaa, T, Lee, KH, 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, BG, Papenberg, G, Papma, J, Parnetti, L, Pasquier, F, Pastor, P, Peters, O, Pijnenburg, YAL, Piñol-Ripoll, G, Popp, J, Porcel, LM, Puerta, R, Pérez-Tur, J, Rainero, I, Ramakers, I, Real, LM, Riedel-Heller, S, Rodriguez-Rodriguez, E, Ross, OA, Royo, JL, 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, EK, Tegos, T, Teunissen, C, Thomassen, JQ, 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, PG, Andreassen, OA, 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, JN, van der Flier, W, Ikeuchi, T, Ramirez, A, Mata, I, Ruiz, A, Gan-Or, Z, Lambert, JC, Greicius, MD & Mignot, E 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. / EADB; GR at 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, 2023.

Research output: Contribution to journal › Article › 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 - EADB

AU - GR at ACE study group

AU - DEGESCO consortium

AU - Demgene

AU - 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 - Leal, Thiago Peixoto

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 - Heilmann-Heimbach, Stefanie

AU - Holstege, Henne

AU - Hort, Jakub

AU - Jung, Yoo Jin

AU - Jürgen, Deckert

AU - Kern, Silke

AU - Kuulasmaa, Teemu

AU - Lee, Kun Ho

AU - Lin, Ling

AU - Masullo, Carlo

AU - Mecocci, Patrizia

AU - Mehrabian, Shima

AU - de Mendonça, Alexandre

AU - Boada, Mercè

AU - Mir, Pablo

AU - Moebus, Susanne

AU - Moreno, Fermin

AU - Nacmias, Benedetta

AU - Nicolas, Gael

AU - Niida, Shumpei

AU - Nordestgaard, Børge G.

AU - Papenberg, Goran

AU - Papma, Janne

AU - Parnetti, Lucilla

AU - Pasquier, Florence

AU - Pastor, Pau

AU - Peters, Oliver

AU - Pijnenburg, Yolande A.L.

AU - Piñol-Ripoll, Gerard

AU - Popp, Julius

AU - Porcel, Laura Molina

AU - Puerta, Raquel

AU - Pérez-Tur, Jordi

AU - Rainero, Innocenzo

AU - Ramakers, Inez

AU - Real, Luis M.

AU - Riedel-Heller, Steffi

AU - Rodriguez-Rodriguez, Eloy

AU - Ross, Owen A.

AU - Royo, Jose Luís

AU - Rujescu, Dan

AU - Scarmeas, Nikolaos

AU - Scheltens, Philip

AU - Scherbaum, Norbert

AU - Schneider, Anja

AU - Seripa, Davide

AU - Skoog, Ingmar

AU - Solfrizzi, Vincenzo

AU - Spalletta, Gianfranco

AU - Squassina, Alessio

AU - van Swieten, John

AU - Sánchez-Valle, Raquel

AU - Tan, Eng King

AU - Tegos, Thomas

AU - Teunissen, Charlotte

AU - Thomassen, Jesper Qvist

AU - Tremolizzo, Lucio

AU - Vyhnalek, Martin

AU - Verhey, Frans

AU - Waern, Margda

AU - Wiltfang, Jens

AU - Zhang, Jing

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - He, Zihuai

AU - Williams, Julie

AU - Amouyel, Philippe

AU - Jessen, Frank

AU - Kehoe, Patrick G.

AU - Andreassen, Ole A.

AU - Van Duin, Cornelia

AU - Tsolaki, Magda

AU - Sánchez-Juan, Pascual

AU - Frikke-Schmidt, Ruth

AU - Sleegers, Kristel

AU - Toda, Tatsushi

AU - Zettergren, Anna

AU - Ingelsson, Martin

AU - Okada, Yukinori

AU - Rossi, Giacomina

AU - Hiltunen, Mikko

AU - Gim, Jungsoo

AU - Ozaki, Kouichi

AU - Sims, Rebecca

AU - Foo, Jia Nee

AU - van der Flier, Wiesje

AU - Ikeuchi, Takeshi

AU - Ramirez, Alfredo

AU - Mata, Ignacio

AU - Ruiz, Agustín

AU - Gan-Or, Ziv

AU - Lambert, Jean Charles

AU - Greicius, Michael D.

AU - Mignot, Emmanuel

PY - 2023

Y1 - 2023

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 - autoimmunity

KW - HLA

KW - neurodegeneration

KW - Parkinson’s disease

UR - http://www.scopus.com/inward/record.url?scp=85168987916&partnerID=8YFLogxK

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 -

EADB, GR at ACE study group, DEGESCO consortium, Demgene, 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;120(36):e2302720120. 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

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