Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by <i>HLA-DRB1*04</i> subtypes-Reference-Cited by-同舟云学术

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

Published:2023-08-29 Issue:36 Volume:120 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Le Guen Yann¹²^ORCID,Luo Guo³,Ambati Aditya³,Damotte Vincent⁴^ORCID,Jansen Iris⁵⁶,Yu Eric⁷⁸⁹,Nicolas Aude⁴,de Rojas Itziar¹⁰¹¹,Peixoto Leal Thiago¹²,Miyashita Akinori¹³,Bellenguez Céline⁴,Lian Michelle Mulan¹⁴¹⁵,Parveen Kayenat¹⁶¹⁷,Morizono Takashi¹⁸,Park Hyeonseul¹⁹,Grenier-Boley Benjamin⁴,Naito Tatsuhiko²⁰²¹,Küçükali Fahri²²²³²⁴,Talyansky Seth D.¹,Yogeshwar Selina Maria³²⁵²⁶,Sempere Vicente³,Satake Wataru²¹,Alvarez Victoria²⁷²⁸,Arosio Beatrice²⁹,Belloy Michael E.¹,Benussi Luisa³⁰,Boland Anne³¹,Borroni Barbara³²,Bullido María J.¹¹³³³⁴,Caffarra Paolo³⁵,Clarimon Jordi¹¹³⁶,Daniele Antonio³⁷³⁸,Darling Daniel³,Debette Stéphanie³⁹⁴⁰,Deleuze Jean-François³¹,Dichgans Martin⁴¹⁴²⁴³,Dufouil Carole⁴⁴⁴⁵,During Emmanuel³^ORCID,Düzel Emrah⁴⁶⁴⁷,Galimberti Daniela⁴⁸⁴⁹,Garcia-Ribas Guillermo⁵⁰,García-Alberca José María¹¹⁵¹,García-González Pablo¹⁰,Giedraitis Vilmantas⁵²⁵³,Goldhardt Oliver⁵⁴,Graff Caroline⁵⁵,Grünblatt Edna⁵⁶⁵⁷⁵⁸,Hanon Olivier⁵⁹,Hausner Lucrezia⁶⁰,Heilmann-Heimbach Stefanie⁶¹,Holstege Henne⁵⁶²,Hort Jakub⁶³⁶⁴^ORCID,Jung Yoo Jin⁶⁵,Jürgen Deckert⁶⁶,Kern Silke⁶⁷⁶⁸,Kuulasmaa Teemu⁶⁹,Lee Kun Ho⁷⁰⁷¹⁷²⁷³⁷⁴,Lin Ling³^ORCID,Masullo Carlo⁷⁵,Mecocci Patrizia⁷⁶,Mehrabian Shima⁷⁷,de Mendonça Alexandre⁷⁸,Boada Mercè¹⁰¹¹,Mir Pablo¹¹⁷⁹,Moebus Susanne⁸⁰,Moreno Fermin¹¹⁸¹⁸²,Nacmias Benedetta⁸³⁸⁴,Nicolas Gael⁸⁵,Niida Shumpei¹⁸^ORCID,Nordestgaard Børge G.⁸⁶⁸⁷,Papenberg Goran⁸⁸,Papma Janne⁸⁹,Parnetti Lucilla⁹⁰,Pasquier Florence⁹¹^ORCID,Pastor Pau⁹²⁹³,Peters Oliver⁹⁴⁹⁵,Pijnenburg Yolande A. L.⁵,Piñol-Ripoll Gerard⁹⁶⁹⁷,Popp Julius⁹⁸⁹⁹¹⁰⁰,Porcel Laura Molina¹⁰¹¹⁰²,Puerta Raquel¹⁰,Pérez-Tur Jordi¹¹¹⁰³¹⁰⁴,Rainero Innocenzo¹⁰⁵,Ramakers Inez¹⁰⁶,Real Luis M.¹⁰⁷¹⁰⁸^ORCID,Riedel-Heller Steffi¹⁰⁹,Rodriguez-Rodriguez Eloy¹¹¹¹⁰,Ross Owen A.¹¹¹¹¹²,Luís Royo Jose¹¹³,Rujescu Dan¹¹⁴^ORCID,Scarmeas Nikolaos¹¹⁵¹¹⁶,Scheltens Philip⁵,Scherbaum Norbert¹¹⁷,Schneider Anja¹¹⁸¹¹⁹,Seripa Davide¹²⁰,Skoog Ingmar⁶⁷¹²¹,Solfrizzi Vincenzo¹²²,Spalletta Gianfranco¹²³¹²⁴^ORCID,Squassina Alessio¹²⁵,van Swieten John¹²⁶,Sánchez-Valle Raquel¹²⁷,Tan Eng-King¹²⁸¹²⁹,Tegos Thomas¹³⁰,Teunissen Charlotte¹³¹,Thomassen Jesper Qvist¹³²,Tremolizzo Lucio¹³³,Vyhnalek Martin⁶²⁶³,Verhey Frans¹³⁴,Waern Margda¹³⁵¹³⁶,Wiltfang Jens¹³⁷¹³⁸¹³⁹,Zhang Jing³,Zetterberg Henrik¹⁴⁰¹⁴¹¹⁴²¹⁴³¹⁴⁴^ORCID,Blennow Kaj¹⁴⁰¹⁴¹,He Zihuai¹,Williams Julie¹⁴⁵¹⁴⁶,Amouyel Philippe⁴,Jessen Frank¹¹⁸¹⁴⁷¹⁴⁸,Kehoe Patrick G.¹⁴⁹,Andreassen Ole A.¹⁵⁰¹⁵¹^ORCID,Van Duin Cornelia¹⁵²¹⁵³,Tsolaki Magda¹³⁰^ORCID,Sánchez-Juan Pascual¹¹¹⁵⁴,Frikke-Schmidt Ruth⁸⁷¹³²,Sleegers Kristel²²²³²⁴,Toda Tatsushi²¹,Zettergren Anna¹³⁵,Ingelsson Martin⁵²⁵³¹⁵⁵¹⁵⁶,Okada Yukinori²⁰¹⁵⁷¹⁵⁸¹⁵⁹,Rossi Giacomina¹⁶⁰,Hiltunen Mikko⁶⁹,Gim Jungsoo¹⁹⁷¹⁷²,Ozaki Kouichi¹⁸¹⁶¹,Sims Rebecca¹⁶²,Foo Jia Nee¹⁴¹⁵^ORCID,van der Flier Wiesje⁵,Ikeuchi Takeshi¹³,Ramirez Alfredo¹⁶¹⁷¹¹⁸¹⁴⁸¹⁶³,Mata Ignacio¹²,Ruiz Agustín¹⁰¹¹,Gan-Or Ziv⁷⁸⁹,Lambert Jean-Charles⁴,Greicius Michael D.¹,Mignot Emmanuel³^ORCID,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 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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 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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, , , , , , ,

Affiliation:

1. Department of Neurology and Neurological Sciences, Stanford University, Stanford 94305, CA

2. Institut du Cerveau–Paris Brain Institute–ICM, Paris 75013, France

3. Center for Sleep Sciences and Medicine, Stanford University, Palo Alto 94304, CA

4. Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liés au vieillissement, Lille 59000, France

5. Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands

6. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije University, 1081 HV Amsterdam, The Netherlands

7. The Neuro (Montreal Neurological Institute-Hospital), Montreal, Quebec H3A 2B4, Canada

8. Department of Human Genetics, McGill University, Montreal, Quebec H3A 0G4, Canada

9. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada

10. Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona 08029, Spain

11. Networking Research Center on Neurodegenerative Diseases (CIRNED), Instituto de Salud Carlos III, Madrid 28029, Spain

12. Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland 44196, OH

13. Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 950-218, Japan

14. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore

15. Laboratory of Neurogenetics, Genome Institute of Singapore, A*STAR, Singapore 138672, Singapore

16. Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany

17. Department of Neurodegenerative diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn 53127, Germany

18. Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan

19. Department of Biomedical Science, Chosun University, Gwangju 61452, Korea

20. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan

21. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 192-0982, Japan

22. Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp 2610, Belgium

23. Laboratory of Neurogenetics, Institute Born–Bunge, Antwerp 2610, Belgium

24. Department of Biomedical Sciences, University of Antwerp, Antwerp 2000, Belgium

25. Department of Neurology, Charité–Universitätsmedizin, Berlin 10117, Germany

26. Charité–Universitätsmedizin Berlin, Einstein Center for Neurosciences Berlin, Berlin 10117, Germany

27. Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo 33011, Spain

28. Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo 33011, Spain

29. Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy

30. Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy

31. Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry 91057, France

32. Department of Clinical and Experimental Sciences, Centre for Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia 25123, Italy

33. Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Universidad Autónoma de Madrid, Madrid 28049, Spain

34. Instituto de Investigacion Sanitaria "Hospital la Paz" (IdIPaz), Madrid 48903, Spain

35. Unit of Neurology, University of Parma and AOU, Parma 43121, Italy

36. Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona 08193, Spain

37. Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome 00168, Italy

38. Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome 00168, Italy

39. University Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux 33000, France

40. Department of Neurology, Bordeaux University Hospital, Bordeaux 33400, France

41. Institute for Stroke and Dementia Research, University Hospital, Ludwig Maximilian University of Munich, 81377, Munich, Germany

42. German Center for Neurodegenerative Diseases, Munich 37075, Germany

43. Munich Cluster for Systems Neurology, Munich 81377, Germany

44. Inserm, Bordeaux Population Health Research Center, UMR 1219, Univ. Bordeaux, ISPED, CIC 1401-EC, Université de Bordeaux, Bordeaux 33405, France

45. CHU de Bordeaux, Pole santé publique, Bordeaux 33400, France

46. German Center for Neurodegenerative Diseases, Magdeburg 39120, Germany

47. Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University, Magdeburg 39106, Germany

48. Neurodegenerative Diseases Unit, Fondazione IRCCS Ca’ Granda, Ospedale Policlinico, Milan 20122, Italy

49. Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan 20122, Italy

50. Hospital Universitario Ramon y Cajal, IRYCIS, Madrid 28034, Spain

51. Alzheimer Research Center and Memory Clinic, Andalusian Institute for Neuroscience, Málaga 29012, Spain

52. Department of Public Health and Caring Sciences, Uppsala University, Uppsala 751 22, Sweden

53. Geriatrics, Uppsala University, Uppsala 751 22, Sweden

54. Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine, Klinikum recs der Isar, Munich 80333, Germany

55. Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital-Solna, Stockholm 171 64, Swdeen

56. Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich 8032, Switzerland

57. Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich 8057, Switzerland

58. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich 8057, Switzerland

59. Université de Paris, EA 4468, APHP, Hôpital Broca, Paris 75013, France

60. Department of Geriatric Psychiatry, Central Institute for Mental Health Mannheim, Faculty Mannheim, University of Heidelberg, Heidelberg 68159, Germany

61. Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn 53127, Germany

62. Department of Clinical Genetics, VU University Medical Centre, Amsterdam 1081 HV, The Netherlands

63. Department of Neurology, Memory Clinic, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague 150 06, Czech Republic

64. International Clinical Research Center, St. Anne’s University Hospital Brno, Brno 656 91, Czech Republic

65. Stanford Neurosciences Interdepartmental Program, Stanford University School of Medicine, Stanford 94305, CA

66. Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg 97080, Germany

67. Department of Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg 405 30, Sweden

68. Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg 413 45, Sweden

69. Institute of Biomedicine, University of Eastern Finland, Joensuu, Kuopio, Eastern Finland 80101, Finland

70. Department of Biomedical Science, Chosun University, Gwangju 61452, Republic of Korea

71. Department of Integrative Biological Sciences, Chosun University, Gwangju 61452, Republic of Korea

72. Gwangju Alzheimer's and Related Dementias Cohort Research Center, Chosun University, Gwangju 61452, Republic of Korea

73. Korea Brain Research Institute, Daegu 41062, Republic of Korea

74. Neurozen Inc., Seoul 06236, Republic of Korea

75. Institute of Neurology, Catholic University of the Sacred Heart, Rome 20123, Italy

76. Department of Medicine and Surgery, Institute of Gerontology and Geriatrics, University of Perugia, Perugia 06123, Italy

77. Clinic of Neurology, UH “Alexandrovska”, Medical University–Sofia, Sofia 1431, Bulgaria

78. Faculty of Medicine, University of Lisbon, Lisbon 1649-028, Portugal

79. Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville 41013, Spain

80. Institute for Urban Public Health, University Hospital of University Duisburg-Essen, Essen 45147, Germany

81. Department of Neurology, Hospital Universitario Donostia, San Sebastian 20014, Spain

82. Neurosciences Area, Instituto Biodonostia, San Sebastian 20014, Spain

83. Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence, Florence 50121, Italy

84. IRCCS Fondazione Don Carlo Gnocchi, Florence 20162, Italy

85. Department of Genetics and CNR-MAJ, Normandie Univ, UNIROUEN, Inserm U1245 and CHU Rouen, Rouen F-76000, France

86. Department of Clinical Biochemistry, Copenhagen University Hospital-Herlev Gentofte, Copenhagen 2730, Denmark

87. Department of Clinical Medicine, University of Copenhagen, Copenhagen 1172, Denmark

88. Department of Neurobiology, Care Sciences and Society, Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm 171 77, Sweden

89. Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam 3000, The Netherlands

90. Centre for Memory Disturbances, Lab of Clinical Neurochemistry, Section of Neurology, University of Perugia, Perugia 06123, Italy

91. Université de Lille, Inserm 1172, CHU Clinical and Research Memory Research Centre of Distalz, Lille 59000, France

92. Fundació Docència i Recerca MútuaTerrassa, Terrassa, Barcelona 08221, Spain

93. Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona 08221, Spain

94. German Center for Neurodegenerative Diseases (DZNE), Berlin 37075, Germany

95. Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Psychiatry and Psychotherapy, Berlin 12203, Germany

96. Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Lleida 25198, Spain

97. Institut de Recerca Biomedica de Lleida, Lleida 25198, Spain

98. Department of Psychiatry, Old Age Psychiatry, Lausanne University Hospital, Lausanne 1005, Switzerland

99. Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich, Zürich 8032, Switzerland

100. Institute for Regenerative Medicine, University of Zürich, Zürich 8952, Switzerland

101. Neurological Tissue Bank–Biobanc- Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain

102. Alzheimer’s disease and other cognitive disorders Unit, Neurology Department, Hospital Clinic, Barcelona 08036, Spain

103. Unitat de Genètica Molecular, Institut de Biomedicina de València-Consejo Superior de Investigaciones Científicas Valencia 46010, Spain

104. Unidad Mixta de Neurologia Genètica, Instituto de Investigación Sanitaria La Fe, Valencia 46026, Spain

105. Department of Neuroscience “Rita Levi Montalcini”, University of Torino, Torino 10126, Italy

106. Department of Psychiatry and Neuropsychologie, Alzheimer Center Limburg, Maastricht University, Maastricht 6229 GS, The Netherlands

107. Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla 41014, Spain

108. Depatamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga 29010, Spain

109. Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig 04109, Germany

110. Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander 39011, Spain

111. Department of Neuroscience, Mayo Clinic-Florida, Jacksonville 32224, FL

112. Department of Clinical Genomics, Mayo Clinic-Florida, Jacksonville 32224, FL

113. Depatamento de Especialidades Quirúrgicas, Bioquímica e Inmunología. Facultad de Medicina, Universidad de Málaga, Málaga 29010, Spain

114. Martin-Luther-University Halle-Wittenberg, University Clinic and Outpatient Clinic for Psychiatry, Psychotherapy and Psychosomatics, Halle (Saale) 06120, Germany

115. Department of Neurology, The Gertrude H. Sergievsky Center, Taub Institute for Research in Alzheimer’s Disease and the Aging Brain, Columbia University, New York 10032, NY

116. 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Medical School, Athens 106 79, Greece

117. Department of Psychiatry and Psychotherapy, Medical Faculty, LVR-Hospital Essen, University of Duisburg-Essen, 45147 Duisberg, Germany

118. German Center for Neurodegenerative Diseases (Deutsches Zentrum für Neurodegenerative Erkrankungen), 37075 Göttingen, Germany

119. Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn 53127, Germany

120. Department of Hematology and Stem Cell Transplant, Laboratory for Advanced Hematological Diagnostics, Lecce 73100, Italy

121. Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg 405 30, Sweden

122. Interdisciry Department of Medicine, Geriatric Medicine and Memory Unit, University of Bari “A. Moro, Bari 70121, Italy

123. Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome 00179, Italy

124. Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston 77030, TX

125. Department of Biomedical Sciences, University of Cagliari, Cagliari 09124, Italy

126. Department of Neurology, ErasmusMC, Rotterdam 3000 CA, Netherlands

127. Alzheimer's disease and other cognitive disorders unit, Service of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona 08036, Spain

128. Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore 308433, Singapore

129. Duke-National University of Singapore Medical School, Singapore 169857, Singapore

130. 1st Department of Neurology, Medical school, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece

131. Neurochemistry Lab, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, Netherlands

132. Department of Clinical Biochemistry, Copenhagen University Hospital–Rigshospitalet, Copenhagen 2100, Denmark

133. Neurology, "San Gerardo" hospital, Monza and University of Milano-Bicocca, Monza 20900, Italy

134. Department of Psychiatry and Neuropsychologie, Alzheimer Center Limburg, Maastricht University, Maastricht 6229 GS, Netherlands

135. Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg 431 41, Sweden

136. Region Västra Götaland, Sahlgrenska University Hospital, Psychosis Clinic, Gothenburg 413 45, Sweden

137. Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Goettingen 37075, Germany

138. German Center for Neurodegenerative Diseases (Deutsches Zentrum für Neurodegenerative Erkrankungen), Goettingen 37075, Germany

139. Department of Medical Sciences, Neurosciences and Signaling Group, Institute of Biomedicine, University of Aveiro, Aveiro 3810-193, Portugal

140. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal 431 41, Sweden

141. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal SE-43180, Sweden

142. Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1E 6BT, United Kingdom

143. UK Dementia Research Institute at UCL, London WC1E 6BT, United Kingdom

144. Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China

145. UKDRI@Cardiff, School of Medicine, Cardiff University, Wales CF14 4YS, United Kingdom

146. Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff Wales CF14 4XN, United Kingdom

147. Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany

148. Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne 50931, Germany

149. Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, United Kingdom

150. NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0450, Norway

151. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

152. Department of Epidemiology, ErasmusMC, Rotterdam 3000 CA, The Netherlands

153. Nuffield Department of Population Health Oxford University, Oxford OX3 7LF, United Kingdom

154. Alzheimer’s Centre Reina Sofia-CIEN Foundation, Madrid, Spain

155. Krembil Brain Institute, University Health Network, Toronto M5G 2C4, Canada

156. Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto M5S 1A8, Canada

157. Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita 565-0871, Japan

158. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita 565-0871, Japan

159. Center for Infectious Disease Education and Research, Osaka University, Suita 565-0871, Japan

160. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy

161. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

162. Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Wales CF14 4YS, United Kingdom

163. Department of Psychiatry and Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio 78229, TX

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.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2302720120

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