Protective association of HLA-DRB1*04 subtypes in neurodegenerative diseases implicates acetylated Tau PHF6 sequences
Authors: Guen Yann Le , Luo Guo , Ambati Aditya , Damotte Vincent , Jansen Iris , Yu Eric , Nicolas Aude , de Rojas Itziar , Leal Thiago Peixoto , 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 , Ling Ling , Masullo Carlo , Mecocci Patrizia , Mehrabian Shima , de Mendonça Alexandre , Boada Mercè , Mir Pablo , Moebus Susanne , Moreno Fermin , Nacmias Benedetta , Nicolas Gael , 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 , 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 , Zetterberg Henrik , Blennow Kaj , Williams Julie , Amouyel Philippe , Jessen Frank , Kehoe Patrick G. , Andreassen Ole , Van Duin Cornelia , Tsolaki Magda , Sánchez-Juan Pascual , Frikke-Schmidt Ruth , Sleegers Kristel , Toda Tatsushi , Zettergren Anna , Ingelsson Martin ,   EABD contributors,   GR@ACE study group,   DEGESCO consortium,   DemGene,   EADI,   GERAD,   Asian Parkinson’s Disease Genetics consortium, 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 
Published: December 2021

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=2.2×10−13; AD: OR=0.91[0.89; 0.93]; p=1.8×10−22), 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.