Journal
MOLECULAR NEURODEGENERATION
Volume 6, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1750-1326-6-54
Keywords
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Funding
- US National Institutes of Health [NIA R01 AG18023]
- Mayo Alzheimer's Disease Research Center [P50 AG16574]
- Mayo Alzheimer's Disease Patient Registry [U01 AG06576]
- US National Institute on Aging [AG25711, AG17216, AG03949]
- National Cell Repository for Alzheimer's Disease (NCRAD)
- National Institute on Aging (NIA) [U24AG21886]
- Alzheimer's Research UK
- Big Lottery Fund
- NIH/NINDS [1RC2NS070276, NS057567, P50NS072187]
- Mayo Clinic Florida (MCF) Research Committee [MCF 90052018, MCF 90052030]
- Dystonia Medical Research Foundation,
- Alzheimers Research UK [ART-PPG2008A-3, ART-SB2010A-1, ART-NCG2008A-1, ART-BIG2009-1] Funding Source: researchfish
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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 epsilon 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 x 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 x 10(-15) (EPHA1) and 1.8 x 10(-13) (CD33).
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