Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study
- Equal contributors
1 Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA
2 School of Molecular Medical Sciences, Institute of Genetics, Queens's Medical Centre, University of Nottingham, NG7 2UH, UK
3 Biostatistics Unit, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA
4 Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
5 Department of Neurology, St. Olav's Hospital, Edvard Griegs Gate 8, 7006 Trondheim, Norway
6 Department of Neuroscience, Norwegian University of Science and Technology, NTNU, 7491 Trondheim, Norway
7 Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
8 Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA
9 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
10 Mayo Alzheimer Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
11 Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, BT7 1NN, UK
12 OB is now affiliated to Hospital de la Santa Creu i Sant Pau, 08025, Barcelona, Spain
Molecular Neurodegeneration 2011, 6:54 doi:10.1186/1750-1326-6-54Published: 28 July 2011
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.
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).
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).