Protective association of HLA-DRB1*04 subtypes in neurodegenerative diseases implicates acetylated tau PHF6 sequences
Authors: Mignot Emmanuel , Guen Yann Le , Luo Guo , Ambati Aditya , Damotte Vincent , Jansen Iris , Yu Eric , Nicolas Aude , de Rojas Itziar , Leal Thiago , Miyashita Akinori , Bellenguez Céline , Lian Michelle , Parveen Kayenat , Morizono Takashi , Park Hyeonseul , Grenier-Boley Benjamin , Naito Tatsuhiko , Küçükali Fahri , Talyansky Seth , Yogeshwar Selina , Sempere Vicente , Sempere Wataru , Álvarez Victoria , Arosio Beatrice , Belloy Michael , Benussi Luisa , Boland Anne , Borroni Barbara , Bullido Maria Jesus , 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 Jose María , García-González Pablo , Giedraitis Vilmantas , Goldhardt Oliver , Graff Caroline , Grünblatt Edna , Hanon Oliver , Hausner Lucrezia , Heilmann-Heimbach Stefanie , Holstege Henne , Hort Jakub , Jung Yoo Jin , Deckert Jürgen , Kern Silke , Kuulasmaa Teemu , Ling Ling , Masullo Carlo , Mecocci Patrizia , Mehrabian Shima , de Mendonça Alexandre , Boada Merce , Mir Pablo , Moebus Susanne , Moreno Fermin , Nacmias Benedetta , Nicolas Gaël , Niida Shumpei , Nordestgaard Børge , Papenberg Goran , Papma Janne , Parnetti Lucilla , Pasquier Florence , Pastor Pau , Peters Oliver , Pijnenburg Yolande , Piñol-Ripoll Gerard , Popp Julius , Molina-Porcel Laura , Fuentes Raquel Puerta , Pérez-Tur Jordi , Rainero Innocenzo , Ramakers Inez , Real Luis , Riedel-Heller Steffi , Rodriguez-Rodriguez Eloy , Royo Jose Luis , Rujescu Dan , Scarmeas Nikolaos , Scheltens Philip , Scherbaum Norbert , Schneider Anja , Seripa Davide , Skoog Ingmar , Solfrizzi Vincenzo , Spalletta Gianfranco , Squassina Alessio , Swieten John van , 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 , Zetterberg Henrik , Blennow Kaj , Williams Julie , Amouyel Philippe , Jessen Frank , Kehoe Patrick , Andreassen Ole , Duijn Cornelia van , tsolaki magda , Sanchez-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 , Flier Wiesje van der , Ikeuchi Takeshi , Ramirez Alfredo , Mata Ignacio , Ruiz Agustín , Gan-Or Ziv , Lee Kun Ho , Lambert Jean-Charles , Greicius Michael 
Published: May 2022

Abstract
Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s (PD) or Alzheimer’s (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. An HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.