6533b852fe1ef96bd12aa326
RESEARCH PRODUCT
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
John HardyNick C. FoxLena LiliusChristine Van BroeckhovenChristine Van BroeckhovenMindy J. KatzCarlos CruchagaJoshua W. MillerCarol BrayneLetizia ConcariLetizia ConcariChristopher E. ShawMinerva M. CarrasquilloRichard MayeuxAnne BolandCharles DecarliHelena C. ChuiLaura B. CantwellYoland Aladro BenitoChuang Kuo WuElaine R. PeskindAndrew McdavidM. Ilyas KambohAmanda SmithPascual Sánchez-juanJean-françois DeleuzeJayanadra J. HimaliThomas H. MosleyThomas J. MontineChuanhai CaoAndreas J. ForstnerThomas G. BeachRobert BarberMiquel AguilarLiming QuJerome I. RotterMatthew J. HuentelmanChristiane ReitzChristopher J. O'donnellSteven G. YounkinBradley T. HymanBruce L. MillerRachelle S. DoodyEric B. LarsonEric B. LarsonRonald L. HamiltonTodd E. GoldeSteven E. ArnoldMelissa E. GarciaRachel RaybouldLena KilanderMark A. SagerKevin MorganKathryn L. LunettaWilliam PerryJoseph D. BuxbaumCraig S. AtwoodThomas D. BirdMichael Conlon O'donovanRobert OlasoJuan ForteaSusanne MoebusLisa L. BarnesRachel MarshallHuntington PotterMercè BoadaShahzad AhmadPaolo CaffarraPaolo CaffarraDaniel C. MarsonJonathan L. HainesPerrie M. AdamsJohn M OlichneyLars LannfeltStefanie Heilmann-heimbachMarkus M. NöthenShubhabrata MukherjeeJohn MalamonXue WangChristopher S. CarlsonKaren RitchieRoger N. RosenbergPaul K. CraneAlexa S. BeiserAlexa S. BeiserCéline BellenguezCéline BellenguezRobert C. GreenMaria UrbanoPetra ProitsiJohn PowellElisa MajounieAmmar Al-chalabiHakon HakonarsonYogen PatelMartin SchererJulie WilliamsRichard B. LiptonVincent DermecourtAdam L. BoxerGerard D. SchellenbergDavid G. ClarkDavid G. ClarkAnita L. DestefanoAnita L. DestefanoJoel H. KramerVictoria AlvarezNandini BadarinarayanOscar L. LopezChris CorcoranUbaldo BonuccelliDonald R. RoyallJames BowenMonica Diez FairenTricia A. Thornton-wellsNilufer Ertekin-tanerFlorence PasquierFlorence PasquierMartin IngelssonYi ZhaoJohn R. GilbertValentina Escott-priceAmanda B. KuzmaFabienne GarziaReinhard HeunOtto ValladaresAndrew J. SaykinSara Ortega-cuberoLiana G. ApostolovaLiana G. ApostolovaLiana G. ApostolovaHenry L. PaulsonJohn K KauweImelda BarberCarolina Ceballos DiazDouglas GalaskoM. Arfan IkramLluís TárragaCarlo CaltagironeJoan S. ReischWolfgang MaierWolfgang MaierBruno VellasRebecca SimsAngela HodgesMatthew P. FroschIsabel HenándezAnnakaisa HaapasaloThor AspelundHåkan ThonbergAimee PierceRoger L. AlbinWayne W. PoonRebecca SussamsAmy BraddelRanjan DuaraAlbert V. SmithKirk C. WilhelmsenGianfranco SpallettaSimon LovestonePeter PassmoreAna Frank-garcíaAna Frank-garcíaCynthia M. CarlssonJade ChapmanNathan D. PricePhilip L. De JagerJohn M. RingmanSeung Hoan ChoiNicola DenningMichael John OwenClinton T. BaldwinAmalia C. BruniDenis A. EvansRudolph E. TanziDominique CampionLaura FratiglioniLaura FratiglioniAlberto LleóPer HoffmannPer HoffmannCarole DufouilCarole DufouilCharlotte ForsellAlun MeggyCharlene ThomasRobert S. SternJames B. LeverenzTatiana ForoudWilliam W. SeeleyJames J. LahBrian A. LawlorKenneth B. FallonMatthias RiemenschneiderRyan M. HuebingerRegina M. CarneyClinton B. WrightDidier HannequinDeborah BlackerAnne Kinhult-ståhlbomEkaterina RogaevaAndrew P. LiebermanBernardino GhettiLinda J. Van EldikBernadette McguinnessThomas FairchildMargaret A. Pericak-vanceAshok RajReinhold SchmidtRonald C. PetersenHarald HampelHarald HampelMaría J. BullidoMaría J. BullidoSteven L. CarrollMaria Candida Deniz NaranjoKathleen A. Welsh-bohmerMyriam FornageJoseph F. QuinnJoseph F. QuinnCaroline GraffClaudia L. SatizabalClaudia L. SatizabalPatrice L. WhiteheadDavid WallonChristopher MedwayLindsay A. FarrerVilmundur GudnasonPeter St George-hyslopPeter St George-hyslopPau PastorFrank JessenFrank JessenFrank JessenErin L. AbnerJohanna JakobsdottirHieab H.h. AdamsRoberta CecchettiWalter A. KukullThomas S. WingoMichelle K. LuptonMichelle K. LuptonValur EmilssonSusan M. MccurrySimon MeadHilkka SoininenSandra WeintraubAmy GerrishLindy E. HarrellLina KellerJean-charles LambertJean-charles LambertDenise HaroldStephen ToddWei GuMaura GalloNajaf AminLenore J. LaunerLenore J. LaunerEleonora SacchinelliMikko HiltunenCécile DularyEliecer CotoXueqiu JianNathalie FievetPatrizia MecocciSarah TaylorEric BoerwinkleEric BoerwinkleMaria SerpenteRonald G. MungerIna GieglingCarlo MasulloAoibhinn LynchEliezer MasliahAnne M. KoivistoChang En YuQiong YangBenedetta NacmiasWayne C. MccormickKristelle BrownAlessio SquassinaDeborah C. MashBrian W. KunkleMakrina DaniilidouAlison GoateDavid CarrellKara L. Hamilton-nelsonSandra BarralVincent ChourakiVincent ChourakiKristel SleegersKristel SleegersFrank J. WoltersJoseph E. ParisiIwona KłoszewskaRonald C. KimSonia Moreno-grauMarina ArcaroCarmen Muñoz FernadezVernon S. PankratzDuane BeeklySabrina PichlerGislain SeptierDelphine BacqAmanda J. MyersAdam C. NajFrank MartiniukSudha SeshadriSudha SeshadriBadri N. VardarajanJoshua A. SonnenM.-marsel MesulamHoward J. RosenJames T. BeckerChiara FenoglioGe LiAlberto PilottoMary SanoOlivier HanonHonghuang LinJean Paul G. VonsattelW. T. LongstrethDaniela GalimbertiDavid C. RubinszteinRosemarie BrundinVilmantas GiedraitisChristine M. HulettePeter HolmansMartin DichgansMartin DichgansMaria VronskayaCéline DerboisMichelangelo MancusoConstantine G. LyketsosChristopher TzourioJacques EpelbaumRaffaele MalettaMariet AllenHong-dong LiJames R. BurkeRik VandenbergheDavid G. MannDavid G. MannBruce M. PsatyLawrence S. HonigBeth A. DombroskiErik D. RobersonCornelia M. Van DuijnBenjamin Grenier-boleyBenjamin Grenier-boleySeppo HelisalmiJean-françois DartiguesRussell H. SwerdlowPaola BossùAshley R. WinslowElio ScarpiniLesley JonesSebastien EngelborghsJohn Q. TrojanowskiJeffrey KayeJeffrey KayeJenny LordChiara CupidiJanet A. JohnstonDan RujescuFeroze GolamaullyAnne BraaeRafael BlesaL. Adrienne CupplesL. Adrienne CupplesDennis W. DicksonGail P. JarvikDavid W. FardoDavid H. CribbsMichael GillJose BrasJose BrasAllan I. LeveyJennifer WilliamsonRhodri ThomasJohn C. MorrisLei YuDebby W. TsuangAnnette M. HartmannJohn H. GrowdonJohn CollingeClaudine BerrFernando RivadeneiraOliver PetersAlbert HofmanFrank M. LaferlaVivianna M. Van DeerlinJames UphillDavid A. BennettOnofre CombarrosGudny EiriksdottirJeremy D. BurgessMelanie L. DunstanElizabeth CroccoKeeley J. BrookesRobert R. GrahamLon S. SchneiderEden R. MartinMatt HillNeill R. Graff-radfordJoseph T. HughesVincenzo SolfrizziTaniesha MorganAntonio CiaramellaBruno DuboisBruno DuboisJuan C. TroncosoPaolo BoscoJordi ClarimónDaniel H. GeschwindVirginia BoccardiBarry ReisbergTimothy W. BehrensAnnette L. FitzpatrickSalvatore SpinaAlexis BriceAlexis BriceEileen H. BigioMarla GearingJeffrey M. BurnsCarol A. MillerMarilyn S. AlbertSven J. Van Der LeeSandro SorbiC. Dirk KeeneDaniel LevyDaniel LevyAntonio DanieleEric M. ReimanParamita ChakrabartyOscar Sotolongo-grauHelena SchmidtFrancesco PanzaMurray A. RaskindRita GuerreiroRita GuerreiroGyungah JunAnna KarydasMarkus LeberHarry V. VintersCory C. FunkCharles C. WhiteJill R. MurrellSid E. O'bryantNigel J. CairnsJosée DupuisAnn C. MckeeJulie A. SchneiderMegan L. GroveMalcolm B. DickBradley F. BoeveJennifer A. BrodySanjay AsthanaAgustín RuizStefan HermsStefan HermsYuning ChenDavid CraigNeil W. KowallMaria Donata OrfeiJoann T. TschanzFlorentino Sanchez GarciaManuel MayhausAlfredo RamirezAlfredo RamirezJames TurtonAndré G. UitterlindenAndré G. UitterlindenDavide SeripaLee-way JinKelley FaberMaria C. NortonShuo LiSteven H. FerrisSteffi G. Riedel-hellerJoshua C. BisLi-san WangJohannes KornhuberPeter Paul De DeynMartin R. FarlowRandall L. WoltjerGary W. Beechamsubject
0301 basic medicineLinkage disequilibrium[SDV]Life Sciences [q-bio]MedizinSequence HomologyGenome-wide association studygenetics [Alzheimer Disease]metabolism [Microglia]Linkage Disequilibrium0302 clinical medicinegenetics [Protein Interaction Maps]genetics [Membrane Glycoproteins]Gene FrequencyImmunologicgenetics [Adaptor Proteins Signal Transducing]Receptorsgenetics [Exome]Odds RatioInnategenetics [Receptors Immunologic]ExomeProtein Interaction Mapsgenetics [Genetic Predisposition to Disease]Receptors ImmunologicABI3 protein humanGeneticsAdaptor Proteins Signal Transducing; Alzheimer Disease; Amino Acid Sequence; Case-Control Studies; Exome; Gene Expression Profiling; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Immunity Innate; Linkage Disequilibrium; Membrane Glycoproteins; Microglia; Odds Ratio; Phospholipase C gamma; Protein Interaction Maps; Receptors Immunologic; Sequence Homology Amino Acid; Polymorphism Single Nucleotide; GeneticsMembrane GlycoproteinsAdaptor ProteinsSingle NucleotideAdaptor Proteins Signal Transducing; Alzheimer Disease; Amino Acid Sequence; Case-Control Studies; Exome; Gene Expression Profiling; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Immunity Innate; Linkage Disequilibrium; Membrane Glycoproteins; Microglia; Odds Ratio; Phospholipase C gamma; Protein Interaction Maps; Receptors Immunologic; Sequence Homology Amino Acid; Polymorphism Single Nucleotide3. Good health[SDV] Life Sciences [q-bio]Amino AcidSettore MED/26 - NEUROLOGIAgenetics [Phospholipase C gamma][SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]MicrogliaAlzheimer's diseaseCommon disease-common variantGenotypeBiologyPolymorphism Single NucleotideArticle03 medical and health sciencesAlzheimer Diseaseddc:570medicineJournal ArticleGeneticsHumansGenetic Predisposition to Disease[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]Amino Acid SequencePolymorphismAllele frequencyAdaptor Proteins Signal TransducingTREM2 protein humanSequence Homology Amino AcidTREM2Phospholipase C gammaGene Expression ProfilingCase-control studySignal TransducingImmunitymedicine.diseaseR1Immunity InnateMinor allele frequencygenetics [Immunity Innate]030104 developmental biologyCase-Control StudiesHuman medicine030217 neurology & neurosurgerydescription
International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-09-01 |