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 GuenGuo LuoAditya AmbatiVincent DamotteIris JansenEric YuAude NicolasItziar de RojasThiago Peixoto LealAkinori MiyashitaCéline BellenguezMichelle Mulan LianKayenat ParveenTakashi MorizonoHyeonseul ParkBenjamin Grenier-BoleyTatsuhiko NaitoFahri KüçükaliSeth D TalyanskySelina Maria YogeshwarVicente SempereWataru SatakeVictoria AlvarezBeatrice ArosioMichael E BelloyLuisa BenussiAnne BolandBarbara BorroniMaría J BullidoPaolo CaffarraJordi ClarimonAntonio DanieleDaniel DarlingStéphanie DebetteJean-François DeleuzeMartin DichgansCarole DufouilEmmanuel H DuringEmrah DüzelDaniela GalimbertiGuillermo Garcia-RibasJosé María García-AlbercaPablo García-GonzálezVilmantas GiedraitisOliver GoldhardtCaroline GraffEdna GrünblattOlivier HanonLucrezia HausnerStefanie Heilmann-HeimbachHenne HolstegeJakub HortYoo Jin JungDeckert JürgenSilke KernTeemu KuulasmaaKun Ho LeeLing LinCarlo MasulloPatrizia MecocciShima MehrabianAlexandre de MendonçaMercè BoadaPablo MirSusanne MoebusFermin MorenoBenedetta NacmiasGael NicolasShumpei NiidaBørge G NordestgaardGoran PapenbergJanne PapmaLucilla ParnettiFlorence PasquierPau PastorOliver PetersYolande A L PijnenburgGerard Piñol-RipollJulius PoppLaura Molina PorcelRaquel PuertaJordi Pérez-TurInnocenzo RaineroInez RamakersLuis Miguel RealSteffi Riedel-HellerEloy Rodriguez-RodriguezOwen A RossJose Luís RoyoDan RujescuNikolaos ScarmeasPhilip ScheltensNorbert ScherbaumAnja SchneiderDavide SeripaIngmar SkoogVincenzo SolfrizziGianfranco SpallettaAlessio SquassinaJohn van SwietenRaquel Sánchez-ValleEng-King TanThomas TegosCharlotte TeunissenJesper Qvist ThomassenLucio TremolizzoMartin VyhnalekFrans VerheyMargda WaernJens WiltfangJing Zhangnull nullnull nullnull nullnull nullnull nullnull nullnull nullHenrik ZetterbergKaj BlennowZihuai HeJulie WilliamsPhilippe AmouyelFrank JessenPatrick G KehoeOle Andreas AndreassenCornelia Van DuinMagdalini TsolakiPascual Sánchez-JuanRuth Frikke-SchmidtKristel SleegersTatsushi TodaAnna ZettergrenMartin IngelssonYukinori OkadaGiacomina RossiMikko HiltunenJungsoo GimKouichi OzakiRebecca SimsJia-Nee FooWiesje van der FlierTakeshi IkeuchiAlfredo RamirezIgnacio MataAgustín RuizZiv Gan-OrJean-Charles LambertMichael D GreiciusEmmanuel Jean-Marie MignotPublished in: Proceedings of the National Academy of Sciences of the United States of America (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.