Journal
ALZHEIMERS RESEARCH & THERAPY
Volume 7, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13195-015-0154-x
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) [R01-NS085419, R01-AG044546, P01-AG003991, R01-AG035083]
- Alzheimer Association [NIRG-11-200110]
- American Federation for Aging Research
- BrightFocus Foundation Alzheimer's Disease Research Grant [A2013359S]
- NIH [P50 AG05681, P01 AG03991, P01 AG026276]
- National Institute on Aging (NIA) [U24 AG21886]
- NIA [U24 AG026395]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (NIH Grant) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- NIA
- National Institute of Biomedical Imaging and Bioengineering
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen Idec, Inc.
- Bristol-Myers Squibb Company
- Eisai, Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd
- Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development, LLC.
- Medpace, Inc.
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer, Inc.
- Piramal Imaging
- Servier
- Synarc, Inc.
- Takeda Pharmaceutical Company
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Introduction: A recent study found a significant increase of ABCA7 loss-of-function variants in Alzheimer's disease (AD) cases compared to controls. Some variants were located on noncoding regions, but it was demonstrated that they affect splicing. Here, we try to replicate the association between AD risk and ABCA7 loss-of-function variants at both the single-variant and gene level in a large and well-characterized European American dataset. Methods: We genotyped the GWAS common variant and four rare variants previously reported for ABCA7 in 3476 European-Americans. Results: We were not able to replicate the association at the single-variant level, likely due to a lower effect size on the European American population which led to limited statistical power. However, we did replicate the association at the gene level; we found a significant enrichment of ABCA7 loss-of-function variants in AD cases compared to controls (P = 0.0388; odds ratio = 1.54). We also confirmed that the association of the loss-of-function variants is independent of the previously reported genome-wide association study signal. Conclusions: Although the effect size for the association of ABCA7 loss-of-function variants with AD risk is lower in our study (odds ratio = 1.54) compared to the original report (odds ratio = 2.2), the replication of the findings of the original report provides a stronger foundation for future functional applications. The data indicate that different independent signals that modify risk for complex traits may exist on the same locus. Additionally, our results suggest that replication of rare-variant studies should be performed at the gene level rather than focusing on a single variant.
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