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 (1) , 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 Talyansky , Selina Maria Yogeshwar , Vicente Sempere , Wataru Satake , Victoria Alvarez , Beatrice Arosio , Michael Belloy , Luisa Benussi , Anne Boland , Barbara Borroni , María 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 Nordestgaard , Goran Papenberg , Janne Papma , Lucilla Parnetti , Florence Pasquier , Pau Pastor , Oliver Peters , Yolande Pijnenburg , Gerard Piñol-Ripoll , Julius Popp , Laura Molina Porcel , Raquel Puerta , Jordi Pérez-Tur , Innocenzo Rainero , Inez Ramakers , Luis Real , Steffi Riedel-Heller , Eloy Rodriguez-Rodriguez , Owen 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 Kehoe , Ole 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 Greicius , Emmanuel Mignot , Céline Bellenguez , Fahri Küçükali , Iris Jansen , Victor Andrade , Sonia Moreno-Grau , Najaf Amin , Benjamin Grenier-Boley , Rafael Campos-Martin , Peter Holmans , Anne Boland , Luca Kleineidam , Vincent Damotte , Sven van der Lee , Teemu Kuulasmaa , Itziar de Rojas , Amber Yaqub , Ivana Prokic , Marcos Costa , Julien Chapuis , Shahzad Ahmad , Vilmantas Giedraitis , Dag Aarsland , Pablo Garcia-Gonzalez , Carla Abdelnour , Emilio Alarcón-Martín , Daniel Alcolea , Montserrat Alegret , Ignacio Alvarez , Victoria Álvarez , Nicola Armstrong , Tsolaki Anthoula , Ildebrando Appollonio , Marina Arcaro , Silvana Archetti , Alfonso Arias Pastor , Beatrice Arosio , Lavinia Athanasiu , Henri Bailly , Nerisa Banaj , Miquel Baquero , Ana Belén Pastor , Luisa Benussi , Claudine Berr , Céline Besse , Valentina Bessi , Giuliano Binetti , Alessandra Bizarro , Rafael Blesa , Mercè Boada , Barbara Borroni , Silvia Boschi , Paola Bossù , Geir Bråthen , Catherine Bresner , Henry Brodaty , Keeley Brookes , Luis Ignacio Brusco , Dolores Buiza-Rueda , Katharina Bûrger , Vanessa Burholt , Miguel Calero , Geneviève Chene , Ángel Carracedo , Roberta Cecchetti , Laura Cervera-Carles , Camille Charbonnier , Caterina Chillotti , Simona Ciccone , Jurgen A.H.R. Claassen , Jordi Clarimon , Christopher Clark , Elisa Conti , Anaïs Corma-Gómez , Emanuele Costantini , Carlo Custodero , Delphine Daian , Maria Carolina Dalmasso , Antonio Daniele , Efthimios Dardiotis , Jean-François Dartigues , Peter Paul de Deyn , Stéphanie Debette , Jürgen Deckert , Teodoro del Ser , Nicola Denning , Martin Dichgans , Janine Diehl-Schmid , Mónica Diez-Fairen , Paolo Dionigi Rossi , Srdjan Djurovic , Emmanuelle Duron , Emrah Düzel , Carole Dufouil , Valentina Escott-Price , Ana Espinosa , Michael Ewers , Marta Fernández-Fuertes , Catarina Ferreira , Evelyn Ferri , Bertrand Fin , Peter Fischer , Tormod Fladby , Klaus Fließbach , Juan Fortea , Silvia Fostinelli , Nick Fox , Emlio Franco-Macías , María Bullido , Ana Frank-García , Lutz Froelich , Daniela Galimberti , Jose Maria García-Alberca , Pablo García-González , Sebastian Garcia-Madrona , Guillermo Garcia-Ribas , Roberta Ghidoni , Ina Giegling , Giaccone Giorgio , Oliver Goldhardt , Antonio González-Pérez , Caroline Graff , Giulia Grande , Emma Green , Timo Grimmer , Edna Grünblatt , Tamar Guetta-Baranes , Annakaisa Haapasalo , Georgios Hadjigeorgiou , Harald Hampel , Olivier Hanon , John Hardy , Annette Hartmann , Lucrezia Hausner , Janet Harwood , Stefanie Heilmann-Heimbach , Seppo Helisalmi , Michael Heneka , Isabel Hernández , Martin Herrmann , Per Hoffmann , Clive Holmes , Henne Holstege , Raquel Huerto Vilas , Marc Hulsman , Charlotte Johansson , Lena Kilander , Anne Kinhult Ståhlbom , Miia Kivipelto , Anne Koivisto , Johannes Kornhuber , Mary Kosmidis , Carmen Lage , Erika Laukka , Alessandra Lauria , Jenni Lehtisalo , Ondrej Lerch , Alberto Lleó , Adolfo Lopez de Munain , Malin Löwemark , Lauren Luckcuck , Juan Macías , Catherine Macleod , Wolfgang Maier , Francesca Mangialasche , Spallazzi Marco , Marta Marquié , Rachel Marshall , Angel Martín Montes , Carmen Martínez Rodríguez , Carlo Masullo , Simon Mead , Patrizia Mecocci , Miguel Medina , Alun Meggy , Shima Mehrabian , Silvia Mendoza , Manuel Menéndez-González , Pablo Mir , Susanne Moebus , Merel Mol , Laura Molina-Porcel , Laura Montrreal , Laura Morelli , Fermin Moreno , Kevin Morgan , Markus Möthen , Carolina Muchnik , Benedetta Nacmias , Tiia Ngandu , Gael Nicolas , Børge Nordestgaard , Robert Olaso , Adelina Orellana , Michela Orsini , Gemma Ortega , Alessandro Padovani , Caffarra Paolo , Goran Papenberg , Lucilla Parnetti , Pau Pastor , Alba Pérez-Cordón , Jordi Pérez-Tur , Pierre Pericard , Oliver Peters , Yolande A.L. Pijnenburg , Juan Pineda , Gerard Piñol-Ripoll , Claudia Pisanu , Thomas Polak , Julius Popp , Danielle Posthuma , Josef Priller , Raquel Puerta , Olivier Quenez , Inés Quintela , Jesper Qvist Thomassen , Alberto Rábano , Innocenzo Rainero , Inez Ramakers , Luis Real , Marcel J.T. Reinders , Steffi Riedel-Heller , Peter Riederer , Natalia Roberto , Eloy Rodriguez-Rodriguez , Arvid Rongve , Irene Rosas Allende , Maitée Rosende-Roca , Jose Luis Royo , Elisa Rubino , Dan Rujescu , María Eugenia Sáez , Paraskevi Sakka , Ingvild Saltvedt , Ángela Sanabria , María Bernal Sánchez-Arjona , Florentino Sanchez-Garcia , Pascual Sánchez Juan , Raquel Sánchez-Valle , Sigrid Sando , Michela Scamosci , Nikolaos Scarmeas , Elio Scarpini , Philip Scheltens , Norbert Scherbaum , Martin Scherer , Matthias Schmid , Anja Schneider , Jonathan Schott , Geir Selbæk , Davide Seripa , Alexey Shadrin , Olivia Skrobot , Hilkka Soininen , Vincenzo Solfrizzi , Alina Solomon , Sandro Sorbi , Oscar Sotolongo-Grau , Gianfranco Spalletta , Annika Spottke , Alessio Squassina , Eystein Stordal , Juan Pablo Tartan , Lluís Tárraga , Niccolo Tesí , Anbupalam Thalamuthu , Tegos Thomas , Latchezar Traykov , Lucio Tremolizzo , Anne Tybjærg-Hansen , Andre Uitterlinden , Abbe Ullgren , Ingun Ulstein , Sergi Valero , Aad van der Lugt , Jasper van Dongen , Jeroen van Rooij , John van Swieten , Rik Vandenberghe , Frans Verhey , Jean-Sébastien Vidal , Jonathan Vogelgsang , Martin Vyhnalek , Michael Wagner , David Wallon , Leonie Weinhold , Jens Wiltfang , Gill Windle , Bob Woods , Mary Yannakoulia , Miren Zulaica , Jan Laczo , Vaclav Matoska , Maria Serpente , Francesca Assogna , Fabrizio Piras , Federica Piras , Valentina Ciullo , Jacob Shofany , Carlo Ferrarese , Simona Andreoni , Gessica Sala , Chiara Paola Zoia , Maria del Zompo , Alberto Benussi , Patrizia Bastiani , Mari Takalo , Teemu Natunen , Tiina Laatikainen , Jaakko Tuomilehto , Riitta Antikainen , Timo Strandberg , Jaana Lindström , Markku Peltonen , Richard Abraham , Ammar Al-Chalabi , Nicholas Bass , Carol Brayne , Kristelle Brown , John Collinge , David Craig , Pangiotis Deloukas , Nick Fox , Amy Gerrish , Michael Gill , Rhian Gwilliam , John Hardy , Denise Harold , Paul Hollingworth , Jarret Johnston , Lesley Jones , Brian Lawlor , Gill Livingston , Simon Lovestone , Michelle Lupton , Aoibhinn Lynch , David Mann , Bernadette Mcguinness , Andrew Mcquillin , Michael O’donovan , Michael Owen , Peter Passmore , John Powell , Petra Proitsi , Martin Rossor , Christopher Shaw , A. David Smith , Hugh Gurling , Stephen Todd , Catherine Mummery , Nathalie Ryan , Giordano Lacidogna , Ad Adarmes-Gómez , Ana Mauleón , Ana Pancho , Anna Gailhajenet , Asunción Lafuente , D Macias-García , Elvira Martín , Esther Pelejà , F Carrillo , Isabel Sastre Merlín , L Garrote-Espina , Liliana Vargas , M Carrion-Claro , M Marín , Ma Labrador , Mar Buendia , María Dolores Alonso , Marina Guitart , Mariona Moreno , Marta Ibarria , Mt Periñán , Nuria Aguilera , P Gómez-Garre , Pilar Cañabate , R Escuela , R Pineda-Sánchez , R Vigo-Ortega , S Jesús , Silvia Preckler , Silvia Rodrigo-Herrero , Susana Diego , Alessandro Vacca , Fausto Roveta , Nicola Salvadori , Elena Chipi , Henning Boecker , Christoph Laske , Robert Perneczky , Costas Anastasiou , Daniel Janowitz , Rainer Malik , Anna Anastasiou , Kayenat Parveen , Carmen Lage , Sara López-García , Anna Antonell , Kalina Yonkova Mihova , Diyana Belezhanska , Heike Weber , Silvia Kochen , Patricia Solis , Nancy Medel , Julieta Lisso , Zulma Sevillano , Daniel Politis , Valeria Cores , Carolina Cuesta , Cecilia Ortiz , Juan Ignacio Bacha , Mario Rios , Aldo Saenz , Mariana Sanchez Abalos , Eduardo Kohler , Dana Lis Palacio , Ignacio Etchepareborda , Matias Kohler , Gisela Novack , Federico Ariel Prestia , Pablo Galeano , Eduardo Castaño , Sandra Germani , Carlos Reyes Toso , Matias Rojo , Carlos Ingino , Carlos Mangone , Sebastiaan Engelborghs , Tagliavini Fabrizio , Sune Fallgaard Nielsen , Lucia Farotti , Chiara Fenoglio , Geert Jan Biessels , Seth Love , Patrick Kehoe , Florence Pasquier , Christine van Broeckhoven , David Rubinsztein , Stefan Teipel , Nathalie Fievet , Vincent Deramecourt , Charlotte Forsell , Håkan Thonberg , Maria Bjerke , Ellen de Roeck , María Teresa Martínez-Larrad , Natividad Olivar , Mohsen Ghanbari , Perminder Sachdev , Karen Mather , Frank Jessen , M. Arfan Ikram , Alexandre de Mendonça , Jakub Hort , Tsolaki Magda , Philippe Amouyel , Julie Williams , Ruth Frikke-Schmidt , Jordi Clarimon , Jean-François Deleuze , Giacomina Rossi , Ole Andreassen , Martin Ingelsson , Mikko Hiltunen , Kristel Sleegers , Cornelia van Duijn , Rebecca Sims , Wiesje van der Flier , Agustín Ruiz , Alfredo Ramirez , Jean-Charles Lambert , N Aguilera , E Alarcon , M Alegret , M Boada , M Buendia , A Cano , P Cañabate , A Carracedo , A Corbatón-Anchuelo , I de Rojas , S Diego , A Espinosa , A Gailhajenet , P García-González , M Guitart , A González-Péerez , M Ibarria , A Lafuente , J Macias , O Maroñas , E Martín , Mt Martínez , M Marquié , L Montrreal , S Moreno-Grau , M Moreno , R. Nuñez-Llaves , C Olivé , A Orellana , G Ortega , A Pancho , E Pelejà , A Pérez-Cordon , Ja Pineda , R Puerta , S Preckler , I Quintela , Lm Real , M Rosende-Roca , A Ruiz , Me Sáez , A Sanabria , M Serrano-Rios , O Sotolongo-Grau , L Táarraga , S Valero , L Vargas , Ad Adarmes-Gómez , E Alarcón-Martín , Md Alonso , I Álvarez , V Álvarez , G Amer-Ferrer , M Antequera , C Antúnez , M Baquero , M Bernal , R Blesa , M Boada , D Buiza-Rueda , Mj Bullido , Ja Burguera , M Calero , F Carrillo , M Carrión-Claro , Mj Casajeros , J Clarimón , Jm Cruz-Gamero , Mm de Pancorbo , I de Rojas , T del Ser , M Diez-Fairen , R Escuela , L Garrote-Espina , J Fortea , E Franco , A Frank-García , Jm García-Alberca , S Garcia Madrona , G Garcia-Ribas , P Gómez-Garre , S Hevilla , S Jesús , Ma Labrador Espinosa , C Lage , A Legaz , A Lleóo , A Lóopez de Munáin , S López-García , D Macias-García , S Manzanares , M Marín , J Marín-Muñoz , T Marín , M Marquié , A Martín Montes , B Martínez , C Martínez , V Martínez , A Martínez-Lage Álvarez , M Medina , M Mendioroz Iriarte , M Menéndez-González , P Mir , L Montrreal , A Orellana , P Pastor , J Péerez Tur , T Periñán-Tocino , R Pineda-Sánchez , G Piñol Ripoll , A Ráabano , D Real de Asúa , S Rodrigo , E Rodríguez-Rodríguez , Jl Royo , A Ruiz , R Sanchez del Valle Díaz , P Sánchez-Juan , I Sastre , O Sotolongo-Grau , S Valero , Mp Vicente , R Vigo-Ortega , L Vivancos , Alexey Shadrin , Shahram Bahrami , Arvid Rongve , Geir Bråthen , Ingunn Bosnes , Eystein Stordal , Lavinia Athanasiu , Per Selnes , Ingvild Saltvedt , Sigrid Sando , Sverre Bergh , Ingun Ulstein , Srdjan Djurovic , Tormod Fladby , Dag Aarsland , Geir Selbæk , Ole Andreassen , Céline Bellenguez , Benjamin Grenier-Boley , Jacques Epelbaum , David Wallon , Didier Hannequin , Florence Pasquier , Claudine Berr , Jean-Francois Dartigues , Dominique Campion , Christophe Tzourio , Vincent Dermecourt , Nathalie Fievet , Olivier Hanon , Carole Dufouil , Alexis Brice , Bruno Dubois , Karen Ritchie , Phillippe Amouyel , Jean-Charles Lambert , Denise Harold , Paul Hollingworth , Rebecca Sims , Amy Gerrish , Nicola Denning , Amy Williams , Charlene Thomas , Alun Meggy , Rachel Marshall , Chloe Davies , Lauren Luckcuck , William Nash , Kimberley Dowzell , Atahualpa Castillo Morales , Mateus Bernardo-Harrington , Patrick Kehoe , Per Hoffmann , Seth Love , James Turton , Jenny Lord , Kristelle Brown , Kevin Morgan , Emma Vardy , Elizabeth Fisher , Jason Warren , Jonathan Schott , Martin Rossor , Natalie Ryan , Nick Fox , Rita Guerreiro , Simon Mead , James Uphill , John Collinge , Michelle Lupton , Ammar Al-Chalabi , Christopher Shaw , Nick Bass , Richard Abraham , Reinhard Heun , Heike Kölsch , Britta Schürmann , Frank Jessen , Wolfgang Maier , Ndré Lacour , Christine Herold , Simon Lovestone , Bernadette Mcguinness , David Craig , Janet Johnston , Michael Gill , Peter Passmore , Stephen Todd , John Powell , Petra Proitsi , Yogen Patel , Angela Hodges , Tim Becker , A. David Smith , Donald Warden , Gordon Wilcock , Robert Clarke , Aoibhinn Lynch , Brian Lawlor , Michael Gill , Andrew Mcquillin , Gill Livingston , John Hardy , David Rubinsztein , Carol Brayne , Rhian Gwilliam , Panagiotis Deloukas , Yoav Ben-Shlomo , David Mann , Nigel Hooper , Stuart Pickering-Brown , Clive Holmes , Rebecca Sussams , Nick Warner , Anthony Bayer , Andrew Singleton , Annette Hartmann , Dan Rujescu , Ina Giegling , Harald Hampel , Martin Dichgans , Isabella Heuser , Dmitriy Drichel , Norman Klopp , Markus Nöthen , Manuel Mayhaus , Matthias Riemenschneider , Sabrina Pinchler , Thomas Feulner , Wei Gu , Hendrik den Bussche , Martin Scherer , Jens Wiltfang , Johannes Kornhuber , Michael Hüll , Lutz Frölich , H-Erich Wichmann , Karl-Heinz Jöckel , Susanne Moebus , Steffi Riedel-Heller , John Kauwe , John Morris , Kevin Mayo , Magda Tsolaki , Michael O’donovan , Lesley Jones , Michael Owen , Valentina Escott-Price , Alfredo Ramirez , Peter Holmans , Julie Williams , Jia Nee Foo , Elaine Guo Yan Chew , Sun Ju Chung , Rong Peng , Yinxia Chao , Louis Cs Tan , Moses Tandiono , Michelle Lian , Ebonne Ng , Kumar-M. Prakash , Wing-Lok Au , Wee-Yang Meah , Shi Qi Mok , Azlina Ahmad Annuar , Anne Yy Chan , Ling Chen , Yongping Chen , Beom Jeon , Lulu Jiang , Jia Lun Lim , Juei-Jueng Lin , Chunfeng Liu , Chengjie Mao , Vincent Mok , Zhong Pei , Hui-Fang Shang , Chang-He Shi , Kyuyoung Song , Ai Huey Tan , Yih-Ru Wu , Yu-Ming Xu , Renshi Xu , Yaping Yan , Jing Yang , Bao Rong Zhang , Woon-Puay Koh , Shen-Yang Lim , Chiea Chuen Khor , Jianjun Liu , Eng-King Tan

1 UI - Universitas Indonesia

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.

Domaines: Chimie

Yann Le Guen, Guo Luo, Aditya Ambati, Vincent Damotte, Iris Jansen, 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), ⟨10.1073/pnas.2302720120⟩. ⟨hal-04286548⟩