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Meta-Analysis
. 2011 May;43(5):429-35.
doi: 10.1038/ng.803. Epub 2011 Apr 3.

Common Variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP Are Associated With Alzheimer's Disease

Paul Hollingworth  1 Denise HaroldRebecca SimsAmy GerrishJean-Charles LambertMinerva M CarrasquilloRichard AbrahamMarian L HamshereJaspreet Singh PahwaValentina MoskvinaKimberley DowzellNicola JonesAlexandra StrettonCharlene ThomasAlex RichardsDobril IvanovCaroline WiddowsonJade ChapmanSimon LovestoneJohn PowellPetroula ProitsiMichelle K LuptonCarol BrayneDavid C RubinszteinMichael GillBrian LawlorAoibhinn LynchKristelle S BrownPeter A PassmoreDavid CraigBernadette McGuinnessStephen ToddClive HolmesDavid MannA David SmithHelen BeaumontDonald WardenGordon WilcockSeth LovePatrick G KehoeNigel M HooperEmma R L C VardyJohn HardySimon MeadNick C FoxMartin RossorJohn CollingeWolfgang MaierFrank JessenEckart RütherBritta SchürmannReiner HeunHeike KölschHendrik van den BusscheIsabella HeuserJohannes KornhuberJens WiltfangMartin DichgansLutz FrölichHarald HampelJohn GallacherMichael HüllDan RujescuIna GieglingAlison M GoateJohn S K KauweCarlos CruchagaPetra NowotnyJohn C MorrisKevin MayoKristel SleegersKarolien BettensSebastiaan EngelborghsPeter P De DeynChristine Van BroeckhovenGill LivingstonNicholas J BassHugh GurlingAndrew McQuillinRhian GwilliamPanagiotis DeloukasAmmar Al-ChalabiChristopher E ShawMagda TsolakiAndrew B SingletonRita GuerreiroThomas W MühleisenMarkus M NöthenSusanne MoebusKarl-Heinz JöckelNorman KloppH-Erich WichmannV Shane PankratzSigrid B SandoJan O AaslyMaria BarcikowskaZbigniew K WszolekDennis W DicksonNeill R Graff-RadfordRonald C PetersenAlzheimer's Disease Neuroimaging InitiativeCornelia M van DuijnMonique M B BretelerM Arfan IkramAnita L DeStefanoAnnette L FitzpatrickOscar LopezLenore J LaunerSudha SeshadriCHARGE consortiumClaudine BerrDominique CampionJacques EpelbaumJean-François DartiguesChristophe TzourioAnnick AlpérovitchMark LathropEADI1 consortiumThomas M FeulnerPatricia FriedrichCaterina RiehleMichael KrawczakStefan SchreiberManuel MayhausS NicolhausStefan WagenpfeilStacy SteinbergHreinn StefanssonKari StefanssonJon SnaedalSigurbjörn BjörnssonPalmi V JonssonVincent ChourakiBenjamin Genier-BoleyMikko HiltunenHilkka SoininenOnofre CombarrosDiana ZelenikaMarc DelepineMaria J BullidoFlorence PasquierIgnacio MateoAna Frank-GarciaElisa PorcelliniOlivier HanonEliecer CotoVictoria AlvarezPaolo BoscoGabriele SicilianoMichelangelo MancusoFrancesco PanzaVincenzo SolfrizziBenedetta NacmiasSandro SorbiPaola BossùPaola PiccardiBeatrice ArosioGiorgio AnnoniDavide SeripaAlberto PilottoElio ScarpiniDaniela GalimbertiAlexis BriceDidier HannequinFederico LicastroLesley JonesPeter A HolmansThorlakur JonssonMatthias RiemenschneiderKevin MorganSteven G YounkinMichael J OwenMichael O'DonovanPhilippe AmouyelJulie Williams
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Free PMC article
Meta-Analysis

Common Variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP Are Associated With Alzheimer's Disease

Paul Hollingworth et al. Nat Genet. .
Free PMC article

Abstract

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

Figures

Figure 1
Figure 1
GERAD+ study design. * Data for rs744373 and rs3818361 in the CHARGE consortium have been presented elsewhere, as has data for rs381861 in the EADI2 samples, as such these SNPs were not included in Stage 3.
Figure 2
Figure 2
Schematic of the associated variants reported in reference to (A) the ABCA7 gene and (B) chromosomal region chr11:59.81Mb-60.1Mb harboring members of the MS4A gene cluster. Chromosome positions are shown at the top of the schematics (UCSC Feb 2009). Gene schematic: horizontal arrows indicate directions of transcription, black boxes indicate gene exons/UTR. The −Log10(P) of the SNPs analyzed in Stage 1 are shown in chart graph. The GERAD+ Stage 1, 2 and 3meta-analysis P-values for SNPs rs3764650 (ABCA7), rs610932 (MS4A6A) and rs670139 (MS4A4E) are indicated by the red lines. The D’ LD block structure of the ABCA7 gene plus surrounding region, and chr11:59.81Mb-60.1Mb according to the CEPH HapMap data, are provided at the bottom of each schematic with lines indicating where each SNP genotyped on the Illumina 610-quad chip is represented.
Figure 3
Figure 3
Forest plots showing association in the different datasets for SNPs at the ABCA7 (rs3764650) and MS4A (rs610932 & rs670139) loci.

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