Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: A multi-centre case-control study

Minerva M. Carrasquillo, Olivia Belbin, Talisha A. Hunter, Li Ma, Gina D. Bisceglio, Fanggeng Zou, Julia E. Crook, V. Pankratz, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Zbigniew K. Wszolek, Dennis W. Dickson, Neill R. Graff-Radford, Ronald C. Petersen, Peter Passmore, Kevin Morgan, Steven G. Younkin

Research output: Contribution to journalArticle

50 Scopus citations

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 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).

Original languageEnglish (US)
Article number54
JournalMolecular neurodegeneration
Volume6
Issue number1
DOIs
StatePublished - 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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