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Abstract
Objectives: CSF levels of Aβ1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aβ1-42, t-tau, p-tau181p, p-tau181p/Aβ1-42, and t-tau/Aβ1-42).
Methods: A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p < 0.01 (uncorrected p < 3.10 × 10−8) and secondarily examined SNPs with uncorrected p values less than 10−5 to identify potential candidates.
Results: Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates.
Conclusions: In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.
Footnotes
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Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. For a complete list of investigators involved in ADNI, see http://www.loni.ucla.edu/ADNI/Collaboration/ADNI_Authorship_list.pdf.
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Study funding: Supported by the NIH (AG024904, AG010129, AG030514, and AG032984), the Dana Foundation, and the Alzheimer's Disease Genetics Consortium. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (NIH U01 AG024904).
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- Aβ1-42
- amyloid-β 1-42 peptide
- AD
- Alzheimer disease
- ADNI
- Alzheimer's Disease Neuroimaging Initiative
- GWAS
- genome-wide association study
- LD
- linkage disequilibrium
- LOAD
- late-onset Alzheimer disease
- MAF
- minor allele frequency
- MCI
- mild cognitive impairment
- p-tau181p
- tau phosphorylated at the threonine 181
- QC
- quality control
- SNP
- single nucleotide polymorphism
- t-tau
- total tau
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Supplemental data at www.neurology.org
- Received April 12, 2010.
- Accepted August 20, 2010.
- Copyright © 2010 by AAN Enterprises, Inc.
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