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, Juliana Crook, V. Pankratz, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff Radford, Ronald Carl Petersen, Peter Passmore, Kevin Morgan, Steven G Younkin

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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

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Case-Control Studies
Alzheimer Disease
Meta-Analysis
Genome-Wide Association Study
Logistic Models
Odds Ratio
Genome
Datasets

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease : A multi-centre case-control study. / Carrasquillo, Minerva M; Belbin, Olivia; Hunter, Talisha A.; Ma, Li; Bisceglio, Gina D.; Zou, Fanggeng; Crook, Juliana; Pankratz, V.; Sando, Sigrid B.; Aasly, Jan O.; Barcikowska, Maria; Wszolek, Zbigniew K; Dickson, Dennis W; Graff Radford, Neill R; Petersen, Ronald Carl; Passmore, Peter; Morgan, Kevin; Younkin, Steven G.

In: Molecular Neurodegeneration, Vol. 6, No. 1, 54, 2011.

Research output: Contribution to journalArticle

Carrasquillo, Minerva M ; Belbin, Olivia ; Hunter, Talisha A. ; Ma, Li ; Bisceglio, Gina D. ; Zou, Fanggeng ; Crook, Juliana ; Pankratz, V. ; Sando, Sigrid B. ; Aasly, Jan O. ; Barcikowska, Maria ; Wszolek, Zbigniew K ; Dickson, Dennis W ; Graff Radford, Neill R ; Petersen, Ronald Carl ; Passmore, Peter ; Morgan, Kevin ; Younkin, Steven G. / Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease : A multi-centre case-control study. In: Molecular Neurodegeneration. 2011 ; Vol. 6, No. 1.
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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).",
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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, Juliana

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 Carl

AU - Passmore, Peter

AU - Morgan, Kevin

AU - Younkin, Steven G

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).

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