Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study
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Published:2011-07-28
Issue:1
Volume:6
Page:
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ISSN:1750-1326
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Container-title:Molecular Neurodegeneration
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language:en
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Short-container-title:Mol Neurodegeneration
Author:
Carrasquillo Minerva M,Belbin Olivia,Hunter Talisha A,Ma Li,Bisceglio Gina D,Zou Fanggeng,Crook Julia E,Pankratz V Shane,Sando Sigrid B,Aasly Jan O,Barcikowska Maria,Wszolek Zbigniew K,Dickson Dennis W,Graff-Radford Neill R,Petersen Ronald C,Passmore Peter,Morgan Kevin,Younkin Steven G,
Abstract
Abstract
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 ε4 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).
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Molecular Biology
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