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PMID: 21460840 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Nature genetics ·Vol. 43 ·No. 5 ·2011-05-00 ·Pages 429-35

Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Rüther E, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Gallacher J, Hüll M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, Alzheimer's Disease Neuroimaging Initiative, van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, CHARGE consortium, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alpérovitch A, Lathrop M, EADI1 consortium, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snaedal J, Björnsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossù P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O'Donovan M, Amouyel P, Williams J

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)).

MeSH Terms
ATP-Binding Cassette Transporters/genetics Adaptor Proteins, Signal Transducing/genetics Aged Aged, 80 and over Alzheimer Disease/genetics Antigens, CD/genetics Antigens, Differentiation, Myelomonocytic/genetics Case-Control Studies Cytoskeletal Proteins/genetics Databases, Genetic Female Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Humans Male Membrane Proteins/genetics Multigene Family Polymorphism, Single Nucleotide Receptor, EphA1/genetics Sialic Acid Binding Ig-like Lectin 3
Chemicals
ABCA7 protein, human ATP-Binding Cassette Transporters Adaptor Proteins, Signal Transducing Antigens, CD Antigens, Differentiation, Myelomonocytic CD2-associated protein CD33 protein, human Cytoskeletal Proteins MS4A4E protein, human Membrane Proteins Sialic Acid Binding Ig-like Lectin 3 Receptor, EphA1
Authors & Affiliations
175 authors, click to expand affiliations / ORCID
Hollingworth Paul
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
Harold Denise
Sims Rebecca
Gerrish Amy
Lambert Jean-Charles
Carrasquillo Minerva M
Abraham Richard
Hamshere Marian L
Pahwa Jaspreet Singh
Moskvina Valentina
Dowzell Kimberley
Jones Nicola
Stretton Alexandra
Thomas Charlene
Richards Alex
Ivanov Dobril
Widdowson Caroline
Chapman Jade
Lovestone Simon
Powell John
Proitsi Petroula
Lupton Michelle K
Brayne Carol
Rubinsztein David C
Gill Michael
Lawlor Brian
Lynch Aoibhinn
Brown Kristelle S
Passmore Peter A
Craig David
McGuinness Bernadette
Todd Stephen
Holmes Clive
Mann David
Smith A David
Beaumont Helen
Warden Donald
Wilcock Gordon
Love Seth
Kehoe Patrick G
Hooper Nigel M
Vardy Emma R L C
Hardy John
Mead Simon
Fox Nick C
Rossor Martin
Collinge John
Maier Wolfgang
Jessen Frank
Rüther Eckart
Schürmann Britta
Heun Reiner
Kölsch Heike
van den Bussche Hendrik
Heuser Isabella
Kornhuber Johannes
Wiltfang Jens
Dichgans Martin
Frölich Lutz
Hampel Harald
Gallacher John
Hüll Michael
Rujescu Dan
Giegling Ina
Goate Alison M
Kauwe John S K
Cruchaga Carlos
Nowotny Petra
Morris John C
Mayo Kevin
Sleegers Kristel
Bettens Karolien
Engelborghs Sebastiaan
De Deyn Peter P
Van Broeckhoven Christine
Livingston Gill
Bass Nicholas J
Gurling Hugh
McQuillin Andrew
Gwilliam Rhian
Deloukas Panagiotis
Al-Chalabi Ammar
Shaw Christopher E
Tsolaki Magda
Singleton Andrew B
Guerreiro Rita
Mühleisen Thomas W
Nöthen Markus M
Moebus Susanne
Jöckel Karl-Heinz
Klopp Norman
Wichmann H-Erich
Pankratz V Shane
Sando Sigrid B
Aasly Jan O
Barcikowska Maria
Wszolek Zbigniew K
Dickson Dennis W
Graff-Radford Neill R
Petersen Ronald C
Alzheimer's Disease Neuroimaging Initiative
van Duijn Cornelia M
Breteler Monique M B
Ikram M Arfan
DeStefano Anita L
Fitzpatrick Annette L
Lopez Oscar
Launer Lenore J
Seshadri Sudha
CHARGE consortium
Berr Claudine
Campion Dominique
Epelbaum Jacques
Dartigues Jean-François
Tzourio Christophe
Alpérovitch Annick
Lathrop Mark
EADI1 consortium
Feulner Thomas M
Friedrich Patricia
Riehle Caterina
Krawczak Michael
Schreiber Stefan
Mayhaus Manuel
Nicolhaus S
Wagenpfeil Stefan
Steinberg Stacy
Stefansson Hreinn
Stefansson Kari
Snaedal Jon
Björnsson Sigurbjörn
Jonsson Palmi V
Chouraki Vincent
Genier-Boley Benjamin
Hiltunen Mikko
Soininen Hilkka
Combarros Onofre
Zelenika Diana
Delepine Marc
Bullido Maria J
Pasquier Florence
Mateo Ignacio
Frank-Garcia Ana
Porcellini Elisa
Hanon Olivier
Coto Eliecer
Alvarez Victoria
Bosco Paolo
Siciliano Gabriele
Mancuso Michelangelo
Panza Francesco
Solfrizzi Vincenzo
Nacmias Benedetta
Sorbi Sandro
Bossù Paola
Piccardi Paola
Arosio Beatrice
Annoni Giorgio
Seripa Davide
Pilotto Alberto
Scarpini Elio
Galimberti Daniela
Brice Alexis
Hannequin Didier
Licastro Federico
Jones Lesley
Holmans Peter A
Jonsson Thorlakur
Riemenschneider Matthias
Morgan Kevin
Younkin Steven G
Owen Michael J
O'Donovan Michael
Amouyel Philippe
Williams Julie
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.803
Published
2011-05-00
Epub
2011-00-03
Pages
429-35
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3084173
Subset
IM
Grants
Medical Research Council · G0801306 · United Kingdom
NIA NIH HHS · U24 AG021886 · United States
Medical Research Council · G0701075 · United Kingdom
NIA NIH HHS · U19 AG010483 · United States
Medical Research Council · G0902227 · United Kingdom
Medical Research Council · G0900688 · United Kingdom
Medical Research Council · G0601846 · United Kingdom
Medical Research Council · G9810900 · United Kingdom
Medical Research Council · MC_G1000734 · United Kingdom
Medical Research Council · G0802189 · United Kingdom
Medical Research Council · MC_U123160651 · United Kingdom
Medical Research Council · G0300429 · United Kingdom
Wellcome Trust · 082604 · United Kingdom
External Links
PubMed source DOI: 10.1038/ng.803 PMC Full Text View journal details
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