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
Authors: Le Guen Yann , Luo Guo , Ambati Aditya , Damotte Vincent , Jansen Iris , Yu Eric , Nicolas Aude , de Rojas Itziar , Peixoto Leal Thiago , Miyashita Akinori , Bellenguez Céline , Lian Michelle Mulan , Parveen Kayenat , Morizono Takashi , Park Hyeonseul , Grenier-Boley Benjamin , Naito Tatsuhiko , Küçükali Fahri , Talyansky Seth D. , Yogeshwar Selina Maria , Sempere Vicente , Satake Wataru , Alvarez Victoria , Arosio Beatrice , Belloy Michael E. , Benussi Luisa , Boland Anne , Borroni Barbara , Bullido María J. , Caffarra Paolo , Clarimon Jordi , Daniele Antonio , Darling Daniel , Debette Stéphanie , Deleuze Jean-François , Dichgans Martin , Dufouil Carole , During Emmanuel , Düzel Emrah , Galimberti Daniela , Garcia-Ribas Guillermo , García-Alberca José María , García-González Pablo , Giedraitis Vilmantas , Goldhardt Oliver , Graff Caroline , Grünblatt Edna , Hanon Olivier , Hausner Lucrezia , Heilmann-Heimbach Stefanie , Holstege Henne , Hort Jakub , Jung Yoo Jin , Jürgen Deckert , Kern Silke , Kuulasmaa Teemu , Lee Kun Ho , Lin Ling , Masullo Carlo , Mecocci Patrizia , Mehrabian Shima , de Mendonça Alexandre , Boada Mercè , Mir Pablo , Moebus Susanne , Moreno Fermin , Nacmias Benedetta , Nicolas Gael , Niida Shumpei , Nordestgaard Børge G. , Papenberg Goran , Papma Janne , Parnetti Lucilla , Pasquier Florence , Pastor Pau , Peters Oliver , Pijnenburg Yolande A. L. , Piñol-Ripoll Gerard , Popp Julius , Porcel Laura Molina , Puerta Raquel , Pérez-Tur Jordi , Rainero Innocenzo , Ramakers Inez , Real Luis M. , Riedel-Heller Steffi , Rodriguez-Rodriguez Eloy , Ross Owen A. , Luís Royo Jose , Rujescu Dan , Scarmeas Nikolaos , Scheltens Philip , Scherbaum Norbert , Schneider Anja , Seripa Davide , Skoog Ingmar , Solfrizzi Vincenzo , Spalletta Gianfranco , Squassina Alessio , van Swieten John , Sánchez-Valle Raquel , Tan Eng-King , Tegos Thomas , Teunissen Charlotte , Thomassen Jesper Qvist , Tremolizzo Lucio , Vyhnalek Martin , Verhey Frans , Waern Margda , Wiltfang Jens , Zhang Jing ,   EADB,   GR@ACE study group,   DEGESCO consortium,   DemGene,   EADI,   GERAD,   Asian Parkinson’s Disease Genetics consortium, Zetterberg Henrik , Blennow Kaj , He Zihuai , Williams Julie , Amouyel Philippe , Jessen Frank , Kehoe Patrick G. , Andreassen Ole A. , Van Duin Cornelia , Tsolaki Magda , Sánchez-Juan Pascual , Frikke-Schmidt Ruth , Sleegers Kristel , Toda Tatsushi , Zettergren Anna , Ingelsson Martin , Okada Yukinori , Rossi Giacomina , Hiltunen Mikko , Gim Jungsoo , Ozaki Kouichi , Sims Rebecca , Foo Jia Nee , van der Flier Wiesje , Ikeuchi Takeshi , Ramirez Alfredo , Mata Ignacio , Ruiz Agustín , Gan-Or Ziv , Lambert Jean-Charles , Greicius Michael D. , Mignot Emmanuel , Bellenguez Céline , Küçükali Fahri , Jansen Iris , Andrade Victor , Moreno-Grau Sonia , Amin Najaf , Grenier-Boley Benjamin , Campos-Martin Rafael , Holmans Peter A. , Boland Anne , Kleineidam Luca , Damotte Vincent , van der Lee Sven J. , Kuulasmaa Teemu , de Rojas Itziar , Yaqub Amber , Prokic Ivana , Costa Marcos R , Chapuis Julien , Ahmad Shahzad , Giedraitis Vilmantas , Aarsland Dag , Garcia-Gonzalez Pablo , Abdelnour Carla , Alarcón-Martín Emilio , Alcolea Daniel , Alegret Montserrat , Alvarez Ignacio , Álvarez Victoria , Armstrong Nicola J. , Anthoula Tsolaki , Appollonio Ildebrando , Arcaro Marina , Archetti Silvana , Arias Pastor Alfonso , Arosio Beatrice , Athanasiu Lavinia , Bailly Henri , Banaj Nerisa , Baquero Miquel , Belén Pastor Ana , Benussi Luisa , Berr Claudine , Besse Céline , Bessi Valentina , Binetti Giuliano , Bizarro Alessandra , Blesa Rafael , Boada Mercè , Borroni Barbara , Boschi Silvia , Bossù Paola , Bråthen Geir , Bresner Catherine , Brodaty Henry , Brookes Keeley J. , Ignacio Brusco Luis , Buiza-Rueda Dolores , BÛrger Katharina , Burholt Vanessa , Calero Miguel , Chene Geneviève , Carracedo Ángel , Cecchetti Roberta , Cervera-Carles Laura , Charbonnier Camille , Chillotti Caterina , Ciccone Simona , Claassen Jurgen A.H.R. , Clarimon Jordi , Clark Christopher , Conti Elisa , Corma-Gómez Anaïs , Costantini Emanuele , Custodero Carlo , Daian Delphine , Dalmasso Maria Carolina , Daniele Antonio , Dardiotis Efthimios , Dartigues Jean-François , de Deyn Peter Paul , Debette Stéphanie , Deckert Jürgen , del Ser Teodoro , Denning Nicola , Dichgans Martin , Diehl-Schmid Janine , Diez-Fairen Mónica , Dionigi Rossi Paolo , Djurovic Srdjan , Duron Emmanuelle , Düzel Emrah , Dufouil Carole , Escott-Price Valentina , Espinosa Ana , Ewers Michael , Fernández-Fuertes Marta , Ferreira Catarina B , Ferri Evelyn , Fin Bertrand , Fischer Peter , Fladby Tormod , Fließbach Klaus , Fortea Juan , Fostinelli Silvia , Fox Nick C. , Franco-Macías Emlio , Bullido María J. , Frank-García Ana , Froelich Lutz , Galimberti Daniela , Maria García-Alberca Jose , García-González Pablo , Garcia-Madrona Sebastian , Garcia-Ribas Guillermo , Ghidoni Roberta , Giegling Ina , Giorgio Giaccone , Goldhardt Oliver , González-Pérez Antonio , Graff Caroline , Grande Giulia , Green Emma , Grimmer Timo , Grünblatt Edna , Guetta-Baranes Tamar , Haapasalo Annakaisa , Hadjigeorgiou Georgios , Hampel Harald , Hanon Olivier , Hardy John , Hartmann Annette M. , Hausner Lucrezia , Harwood Janet , Heilmann-Heimbach Stefanie , Helisalmi Seppo , Heneka Michael T. , Hernández Isabel , Herrmann Martin J. , Hoffmann Per , Holmes Clive , Holstege Henne , Huerto Vilas Raquel , Hulsman Marc , Johansson Charlotte , Kilander Lena , Kinhult Ståhlbom Anne , Kivipelto Miia , Koivisto Anne , Kornhuber Johannes , Kosmidis Mary H. , Lage Carmen , Laukka Erika J , Lauria Alessandra , Lehtisalo Jenni , Lerch Ondrej , Lleó Alberto , de Munain Adolfo Lopez , Löwemark Malin , Luckcuck Lauren , Macías Juan , MacLeod Catherine A. , Maier Wolfgang , Mangialasche Francesca , Marco Spallazzi , Marquié Marta , Marshall Rachel , Martín Montes Angel , Martínez Rodríguez Carmen , Masullo Carlo , Mead Simon , Mecocci Patrizia , Medina Miguel , Meggy Alun , Mehrabian Shima , Mendoza Silvia , Menéndez-González Manuel , Mir Pablo , Moebus Susanne , Mol Merel , Molina-Porcel Laura , Montrreal Laura , Morelli Laura , Moreno Fermin , Morgan Kevin , Möthen Markus M , Muchnik Carolina , Nacmias Benedetta , Ngandu Tiia , Nicolas Gael , Nordestgaard Børge G. , Olaso Robert , Orellana Adelina , Orsini Michela , Ortega Gemma , Padovani Alessandro , Paolo Caffarra , Papenberg Goran , Parnetti Lucilla , Pastor Pau , Pérez-Cordón Alba , Pérez-Tur Jordi , Pericard Pierre , Peters Oliver , Pijnenburg Yolande A.L. , Pineda Juan A , Piñol-Ripoll Gerard , Pisanu Claudia , Polak Thomas , Popp Julius , Posthuma Danielle , Priller Josef , Puerta Raquel , Quenez Olivier , Quintela Inés , Qvist Thomassen Jesper , Rábano Alberto , Rainero Innocenzo , Ramakers Inez , Real Luis M , Reinders Marcel J.T. , Riedel-Heller Steffi , Riederer Peter , Roberto Natalia , Rodriguez-Rodriguez Eloy , Rongve Arvid , Rosas Allende Irene , Rosende-Roca Maitée , Luis Royo Jose , Rubino Elisa , Rujescu Dan , Eugenia Sáez María , Sakka Paraskevi , Saltvedt Ingvild , Sanabria Ángela , Sánchez-Arjona María Bernal , Sanchez-Garcia Florentino , Sánchez Juan Pascual , Sánchez-Valle Raquel , Sando Sigrid B , Scamosci Michela , Scarmeas Nikolaos , Scarpini Elio , Scheltens Philip , Scherbaum Norbert , Scherer Martin , Schmid Matthias , Schneider Anja , Schott Jonathan M. , Selbæk Geir , Seripa Davide , Shadrin Alexey A , Skrobot Olivia , Soininen Hilkka , Solfrizzi Vincenzo , Solomon Alina , Sorbi Sandro , Sotolongo-Grau Oscar , Spalletta Gianfranco , Spottke Annika , Squassina Alessio , Stordal Eystein , Pablo Tartan Juan , Tárraga Lluís , Tesí Niccolo , Thalamuthu Anbupalam , Thomas Tegos , Traykov Latchezar , Tremolizzo Lucio , Tybjærg-Hansen Anne , Uitterlinden Andre , Ullgren Abbe , Ulstein Ingun , Valero Sergi , van der Lugt Aad , Van Dongen Jasper , van Rooij Jeroen , van Swieten John , Vandenberghe Rik , Verhey Frans , Vidal Jean-Sébastien , Vogelgsang Jonathan , Vyhnalek Martin , Wagner Michael , Wallon David , Weinhold Leonie , Wiltfang Jens , Windle Gill , Woods Bob , Yannakoulia Mary , Zulaica Miren , Laczo Jan , Matoska Vaclav , Serpente Maria , Assogna Francesca , Piras Fabrizio , Piras Federica , Ciullo Valentina , Shofany Jacob , Ferrarese Carlo , Andreoni Simona , Sala Gessica , Paola Zoia Chiara , Del Zompo Maria , Benussi Alberto , Bastiani Patrizia , Takalo Mari , Natunen Teemu , Laatikainen Tiina , Tuomilehto Jaakko , Antikainen Riitta , Strandberg Timo , Lindström Jaana , Peltonen Markku , Abraham Richard , Al-Chalabi Ammar , Bass Nicholas J. , Brayne Carol , Brown Kristelle S. , Collinge John , Craig David , Deloukas Pangiotis , Fox Nick , Gerrish Amy , Gill Michael , Gwilliam Rhian , Hardy John , Harold Denise , Hollingworth Paul , Johnston Jarret A. , Jones Lesley , Lawlor Brian , Livingston Gill , Lovestone Simon , Lupton Michelle , Lynch Aoibhinn , Mann David , McGuinness Bernadette , McQuillin Andrew , O’Donovan Michael C. , Owen Michael J. , Passmore Peter , Powell John F , Proitsi Petra , Rossor Martin , Shaw Christopher E. , David Smith A. , Gurling Hugh , Todd Stephen , Mummery Catherine , Ryan Nathalie , Lacidogna Giordano , Adarmes-Gómez Ad , Mauleón Ana , Pancho Ana , Gailhajenet Anna , Lafuente Asunción , Macias-García D , Martín Elvira , Pelejà Esther , Carrillo F , Sastre Merlín Isabel , Garrote-Espina L , Vargas Liliana , Carrion-Claro M , Marín M , Labrador Ma , Buendia Mar , Dolores Alonso María , Guitart Marina , Moreno Mariona , Ibarria Marta , Periñán Mt , Aguilera Nuria , Gómez-Garre P , Cañabate Pilar , Escuela R , Pineda-Sánchez R , Vigo-Ortega R , Jesús S , Preckler Silvia , Rodrigo-Herrero Silvia , Diego Susana , Vacca Alessandro , Roveta Fausto , Salvadori Nicola , Chipi Elena , Boecker Henning , Laske Christoph , Perneczky Robert , Anastasiou Costas , Janowitz Daniel , Malik Rainer , Anastasiou Anna , Parveen Kayenat , Lage Carmen , López-García Sara , Antonell Anna , Yonkova Mihova Kalina , Belezhanska Diyana , Weber Heike , Kochen Silvia , Solis Patricia , Medel Nancy , Lisso Julieta , Sevillano Zulma , Politis Daniel G , Cores Valeria , Cuesta Carolina , Ortiz Cecilia , Ignacio Bacha Juan , Rios Mario , Saenz Aldo , Sanchez Abalos Mariana , Kohler Eduardo , Lis Palacio Dana , Etchepareborda Ignacio , Kohler Matias , Novack Gisela , Ariel Prestia Federico , Galeano Pablo , Castaño Eduardo M. , Germani Sandra , Reyes Toso Carlos , Rojo Matias , Ingino Carlos , Mangone Carlos , Engelborghs Sebastiaan , Fabrizio Tagliavini , Fallgaard Nielsen Sune , Farotti Lucia , Fenoglio Chiara , Jan Biessels Geert , Love Seth , Kehoe Patrick G. , Pasquier Florence , Van Broeckhoven Christine , Rubinsztein David C. , Teipel Stefan , Fievet Nathalie , Deramecourt Vincent , Forsell Charlotte , Thonberg Håkan , Bjerke Maria , De Roeck Ellen , Teresa Martínez-Larrad María , Olivar Natividad , Ghanbari Mohsen , Sachdev Perminder , Mather Karen , Jessen Frank , Arfan Ikram M. , de Mendonça Alexandre , Hort Jakub , Magda Tsolaki , Amouyel Philippe , Williams Julie , Frikke-Schmidt Ruth , Clarimon Jordi , Deleuze Jean-François , Rossi Giacomina , Andreassen Ole A. , Ingelsson Martin , Hiltunen Mikko , Sleegers Kristel , van Duijn Cornelia M. , Sims Rebecca , van der Flier Wiesje M. , Ruiz Agustín , Ramirez Alfredo , Lambert Jean-Charles , Aguilera N , Alarcon E , Alegret M , Boada M , Buendia M , Cano A , Cañabate P , Carracedo A , Corbatón-Anchuelo A , de Rojas I , Diego S , Espinosa A , Gailhajenet A , García-González P , Guitart M , González-Péerez A , Ibarria M , Lafuente A , Macias J , Maroñas O , Martín E , Martínez MT , Marquié M , Montrreal L , Moreno-Grau S , Moreno M , Nuñez-Llaves R. , Olivé C , Orellana A , Ortega G , Pancho A , Pelejà E , Pérez-Cordon A , Pineda JA , Puerta R , Preckler S , Quintela I , Real LM , Rosende-Roca M , Ruiz A , Sáez ME , Sanabria A , Serrano-Rios M , Sotolongo-Grau O , Táarraga L , Valero S , Vargas L , Adarmes-Gómez AD , Alarcón-Martín E , Alonso MD , Álvarez I , Álvarez V , Amer-Ferrer G , Antequera M , Antúnez C , Baquero M , Bernal M , Blesa R , Boada M , Buiza-Rueda D , Bullido MJ , Burguera JA , Calero M , Carrillo F , Carrión-Claro M , Casajeros MJ , Clarimón J , Cruz-Gamero JM , de Pancorbo MM , de Rojas I , del Ser T , Diez-Fairen M , Escuela R , Garrote-Espina L , Fortea J , Franco E , Frank-García A , García-Alberca JM , Garcia Madrona S , Garcia-Ribas G , Gómez-Garre P , Hevilla S , Jesús S , Labrador Espinosa MA , Lage C , Legaz A , Lleóo A , Lóopez de Munáin A , López-García S , Macias-García D , Manzanares S , Marín M , Marín-Muñoz J , Marín T , Marquié M , Martín Montes A , Martínez B , Martínez C , Martínez V , Martínez-Lage Álvarez A , Medina M , Mendioroz Iriarte M , Menéndez-González M , Mir P , Montrreal L , Orellana A , Pastor P , Péerez Tur J , Periñán-Tocino T , Pineda-Sánchez R , Piñol Ripoll G , Ráabano A , Real de Asúa D , Rodrigo S , Rodríguez-Rodríguez E , Royo JL , Ruiz A , Sanchez del Valle Díaz R , Sánchez-Juan P , Sastre I , Sotolongo-Grau O , Valero S , Vicente MP , Vigo-Ortega R , Vivancos L , Shadrin Alexey A , Bahrami Shahram , Rongve Arvid , Bråthen Geir , Bosnes Ingunn , Stordal Eystein , Athanasiu Lavinia , Selnes Per , Saltvedt Ingvild , Sando Sigrid B. , Bergh Sverre , Ulstein Ingun , Djurovic Srdjan , Fladby Tormod , Aarsland Dag , Selbæk Geir , Andreassen Ole A. , Bellenguez Céline , Grenier-Boley Benjamin , Epelbaum Jacques , Wallon David , Hannequin Didier , Pasquier Florence , Berr Claudine , Dartigues Jean-Francois , campion Dominique , Tzourio Christophe , Dermecourt Vincent , Fievet Nathalie , Hanon Olivier , Dufouil Carole , Brice Alexis , Dubois Bruno , Ritchie Karen , Amouyel Phillippe , Lambert Jean-Charles , Harold Denise , Hollingworth Paul , Sims Rebecca , Gerrish Amy , Denning Nicola , Williams Amy , Thomas Charlene , Meggy Alun , Marshall Rachel , Davies Chloe , Luckcuck Lauren , Nash William , Dowzell Kimberley , Castillo Morales Atahualpa , Bernardo-Harrington Mateus , Kehoe Patrick , Hoffmann Per , Love Seth , Turton James , Lord Jenny , Brown Kristelle , Morgan Kevin , Vardy Emma , Fisher Elizabeth , Warren Jason D. , Schott Jonathan M. , Rossor Martin , Ryan Natalie S. , Fox Nick C. , Guerreiro Rita , Mead Simon , Uphill James , Collinge John , Lupton Michelle , Al-Chalabi Ammar , Shaw Christopher E. , Bass Nick , Abraham Richard , Heun Reinhard , Kölsch Heike , Schürmann Britta , Jessen Frank , Maier Wolfgang , Lacour ndré , Herold Christine , Lovestone Simon , McGuinness Bernadette , Craig David , Johnston Janet A. , Gill Michael , Passmore Peter , Todd Stephen , Powell John , Proitsi Petra , Patel Yogen , Hodges Angela , Becker Tim , David Smith A. , Warden Donald , Wilcock Gordon , Clarke Robert , Lynch Aoibhinn , Lawlor Brian , Gill Michael , McQuillin Andrew , Livingston Gill , Hardy John , Rubinsztein David C. , Brayne Carol , Gwilliam Rhian , Deloukas Panagiotis , Ben-Shlomo Yoav , Mann David , Hooper Nigel M. , Pickering-Brown Stuart , Holmes Clive , Sussams Rebecca , Warner Nick , Bayer Anthony , Singleton Andrew B. , Hartmann Annette M , Rujescu Dan , Giegling Ina , Hampel Harald , Dichgans Martin , Heuser Isabella , Drichel Dmitriy , Klopp Norman , Nöthen Markus M. , Mayhaus Manuel , Riemenschneider Matthias , Pinchler Sabrina , Feulner Thomas , Gu Wei , den Bussche Hendrik , Scherer Martin , Wiltfang Jens , Kornhuber Johannes , Hüll Michael , Frölich Lutz , Wichmann H-Erich , Jöckel Karl-Heinz , Moebus Susanne , Riedel-Heller Steffi , Kauwe John , Morris John , Mayo Kevin , Tsolaki Magda , O’Donovan Michael , Jones Lesley , Owen Michael , Escott-Price Valentina , Ramirez Alfredo , Holmans Peter , Williams Julie , Foo Jia Nee , Chew Elaine Guo Yan , Chung Sun Ju , Peng Rong , Chao Yinxia , Tan Louis CS , Tandiono Moses , Lian Michelle M , Ng Ebonne Y , Prakash Kumar-M. , Au Wing-Lok , Meah Wee-Yang , Mok Shi Qi , Annuar Azlina Ahmad , Chan Anne YY , Chen Ling , Chen Yongping , Jeon Beom S , Jiang Lulu , Lim Jia Lun , Lin Juei-Jueng , Liu Chunfeng , Mao Chengjie , Mok Vincent , Pei Zhong , Shang Hui-Fang , Shi Chang-He , Song Kyuyoung , Tan Ai Huey , Wu Yih-Ru , Xu Yu-ming , Xu Renshi , Yan Yaping , Yang Jing , Rong Zhang Bao , Koh Woon-Puay , Lim Shen-Yang , Khor Chiea Chuen , Liu Jianjun , Tan Eng-King 
Published: August 2023

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.