Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
Rebecca SimsSven J Van der LeeAdam C NajCéline BellenguezNandini BadarinarayanJohanna JakobsdottirBrian W KunkleAnne BolandRachel RaybouldJoshua C BisEden R MartinBenjamin Grenier-BoleyStefanie Heilmann-HeimbachVincent ChourakiAmanda B KuzmaKristel SleegersMaria VronskayaAgustin RuizRobert R GrahamRobert OlasoPer HoffmannMegan L GroveBadri N VardarajanMikko HiltunenMarkus M NöthenCharles C WhiteKara L Hamilton-NelsonJacques EpelbaumWolfgang MaierSeung-Hoan ChoiGary W BeechamCécile DularyStefan HermsAlbert Vernon SmithCory C FunkCéline DerboisAndreas J ForstnerShahzad AhmadHongdong LiDelphine BacqDenise HaroldClaudia L SatizabalOtto ValladaresAlessio SquassinaRhodri ThomasJennifer A BrodyLiming QuPascual Sánchez-JuanTaniesha MorganSirwan K L DarweeshYi ZhaoFlorentino Sanchez GarciaNicola DenningMyriam FornageJohn MalamonMaria Candida Deniz NaranjoElisa MajounieThomas H MosleyBeth DombroskiDavid WallonMichelle K LuptonJosée DupuisPatrice WhiteheadLaura FratiglioniChristopher MedwayXueqiu JianShubhabrata MukherjeeLina KellerKristelle BrownHonghuang LinLaura B CantwellFrancesco PanzaBernadette McGuinnessSonia Moreno-GrauJeremy D BurgessVincenzo SolfrizziPetra ProitsiHieab H H AdamsMariet AllenDavide SeripaPau PastorL Adrienne CupplesNathan D PriceDidier HannequinAna Frank-GarcíaDaniel LevyParamita ChakrabartyPaolo CaffarraIna GieglingAlexa S BeiserVilmantas GiedraitisHarald HampelMelissa E GarciaXue WangLars LannfeltPatrizia MecocciGudny EiriksdottirPaul K CraneFlorence PasquierVirginia BoccardiIsabel HenándezRobert C BarberMartin SchererLluis TarragaPerrie M AdamsMarkus LeberYuning ChenMarilyn S AlbertSteffi Riedel-HellerValur EmilssonDuane BeeklyAnne BraaeReinhold SchmidtDeborah BlackerCarlo MasulloHelena SchmidtRachelle S DoodyGianfranco SpallettaW T LongstrethThomas J FairchildPaola BossùOscar L LopezMatthew P FroschEleonora SacchinelliBernardino F GhettiQiong YangRyan M HuebingerFrank JessenShuo LiM Ilyas KambohJohn MorrisOscar Sotolongo-GrauMindy J KatzChris CorcoranMelanie DunstanAmy BraddelCharlene ThomasAlun MeggyRachel MarshallAmy GerrishJade ChapmanMiquel AguilarSarah TaylorMatt HillMònica Díez FairénAngela HodgesBruno VellasHilkka SoininenIwona KloszewskaMakrina DaniilidouJames UphillYogen PatelJoseph T HughesJenny LordJames TurtonAnnette M HartmannRoberta CecchettiChiara FenoglioMaria SerpenteMarina ArcaroCarlo CaltagironeMaria Donata OrfeiAntonio CiaramellaSabrina PichlerManuel MayhausWei GuAlberto LleóJuan ForteaRafael BlesaImelda S BarberKeeley BrookesChiara CupidiRaffaele Giovanni MalettaDavid CarrellSandro SorbiSusanne MoebusMaria UrbanoAlberto PilottoJohannes KornhuberPaolo BoscoStephen ToddDavid CraigJanet JohnstonMichael GillBrian LawlorAoibhinn LynchNick C FoxJohn Hardynull nullRoger L AlbinLiana G ApostolovaSteven E ArnoldSanjay AsthanaCraig S AtwoodClinton T BaldwinLisa L BarnesSandra BarralThomas G BeachJames T BeckerEileen H BigioThomas D BirdBradley F BoeveJames D BowenAdam BoxerJames R BurkeJeffrey M BurnsJoseph D 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KoivistoAnnakaisa HaapasaloVincent DermecourtNathalie FievetOlivier HanonCarole DufouilAlexis BriceKaren RitchieBruno DuboisJayanadra J HimaliC Dirk KeeneJoAnn TschanzAnnette L FitzpatrickWalter A KukullMaria NortonThor AspelundEric B LarsonRon MungerJerome I RotterRichard B LiptonMaria Jesus BullidoAlbert HofmanThomas J MontineEliecer CotoEric BoerwinkleRonald C PetersenVictoria AlvarezFernando RivadeneiraEric M ReimanMaura GalloChristopher J O'DonnellJoan S ReischAmalia Cecilia BruniDonald R RoyallMartin DichgansMary SanoDaniela GalimbertiPeter St George-HyslopElio ScarpiniDebby W TsuangMichelangelo MancusoUbaldo BonuccelliAshley R WinslowAntonio DanieleChuang-Kuo Wunull nullOliver PetersBenedetta NacmiasMatthias RiemenschneiderReinhard HeunCarol BrayneDavid C RubinszteinJose BrasRita GuerreiroAmmar Al ChalabiChristopher E ShawJohn CollingeDavid MannMagdalini TsolakiJordi ClarimónRebecca SussamsSimon LovestoneMichael C O'DonovanMichael J OwenTimothy W BehrensSimon MeadAlison M GoateAndre G UitterlindenClive HolmesCarlos CruchagaMartin IngelssonDavid A BennettJohn PowellTodd E GoldeCaroline GraffPhilip Lawrence De JagerKevin MorganNilufer Ertekin-TanerOnofre CombarrosBruce M PsatyPeter PassmoreSteven G YounkinClaudine BerrVilmundur GudnasonDan RujescuGourisankar GhoshJean-François DartiguesAnita L DeStefanoSara Ortega-CuberoHakon HakonarsonDominique CampionMerce BoadaJohn Keoni KauweLindsay A FarrerChristine Van BroeckhovenMohammad Arfan IkramLesley JonesJonathan L HainesChristophe TzourioLenore J LaunerValentina Escott-PriceRichard MayeuxJean-François DeleuzeNajaf AminPeter A HolmansMargaret A Pericak-VancePhillippe AmouyelCornelia M van DuijnAlfredo RamirezLi-San WangJean-Charles LambertSudha SeshadriJulie WilliamsGerard D SchellenbergPublished in: Nature genetics (2017)
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.