TY - JOUR
T1 - Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease
T2 - A multi-centre case-control study
AU - Carrasquillo, Minerva M.
AU - Belbin, Olivia
AU - Hunter, Talisha A.
AU - Ma, Li
AU - Bisceglio, Gina D.
AU - Zou, Fanggeng
AU - Crook, Julia E.
AU - Pankratz, V.
AU - Sando, Sigrid B.
AU - Aasly, Jan O.
AU - Barcikowska, Maria
AU - Wszolek, Zbigniew K.
AU - Dickson, Dennis W.
AU - Graff-Radford, Neill R.
AU - Petersen, Ronald C.
AU - Passmore, Peter
AU - Morgan, Kevin
AU - Younkin, Steven G.
N1 - Funding Information:
We thank contributors, including the Alzheimer’s disease centers who collected samples used in this study, as well as subjects and their families, whose help and participation made this work possible. We thank the members of the Alzheimer’s Research UK (ARUK) consortium who contributed samples to the ARUK resource. This work was supported by grants from the US National Institutes of Health, NIA R01 AG18023 (NRG-R, SGY); Mayo Alzheimer’s Disease Research Center, P50 AG16574 (RCP, DWD, NRG-R, SGY); Mayo Alzheimer’s Disease Patient Registry, U01 AG06576 (RCP); and US National Institute on Aging, AG25711, AG17216, AG03949 (DWD). Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24AG21886) awarded by the National Institute on Aging (NIA), were used in this study. This project was also generously supported by the Robert and Clarice Smith Postdoctoral Fellowship (MMC); Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program (RCP, DWD, NRG-R, SGY) and by the Palumbo Professorship in Alzheimer’s Disease Research (SGY). KM is funded by the Alzheimer’s Research UK and the Big Lottery Fund. ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052018 and MCF #90052030), Dystonia Medical Research Foundation, and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Alzheimer’s Research UK Consortium: Peter Passmore, David Craig, Janet Johnston, Bernadette McGuinness, Stephen Todd, Queen’s University Belfast, UK; Reinhard Heun (now at Royal Derby Hospital), Heike Kölsch, University of Bonn, Germany; Patrick G. Kehoe, University of Bristol, UK; Nigel M. Hooper, Emma R.L.C. Vardy (now at University of Newcastle), University of Leeds, UK; David M. Mann, University of Manchester, UK; Kristelle Brown, Noor Kalsheker, Kevin Morgan, University of Nottingham, UK; A. David Smith, Gordon Wilcock, Donald Warden, University of Oxford (OPTIMA), UK, Clive Holmes, University of Southampton, UK.
PY - 2011
Y1 - 2011
N2 - Background: A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE 4 dosage. Results: We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10 -4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56). Conclusions: Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10 -15 (EPHA1) and 1.8 × 10 -13 (CD33).
AB - Background: A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE 4 dosage. Results: We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10 -4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56). Conclusions: Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10 -15 (EPHA1) and 1.8 × 10 -13 (CD33).
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U2 - 10.1186/1750-1326-6-54
DO - 10.1186/1750-1326-6-54
M3 - Article
C2 - 21798052
AN - SCOPUS:79960654507
SN - 1750-1326
VL - 6
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 54
ER -