Journal
NEUROLOGY
Volume 76, Issue 1, Pages 69-79Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e318204a397
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Funding
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (NIH) [U01 AG024904]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- NIH [P30 AG010129, K01 AG030514, NIBIB R03 EB008674, NIBIB R03 EB008674S1, UL1 RR025761, NLM T15LM07117, NIA 5U24AG021886, R01AR047822, R01NS037167, N01NS32357]
- Dana Foundation
- National Institute on Aging (NIA) [U24 AG21886]
- Families of Spinal Muscular Atrophy
- Muscular Dystrophy Association
- HP Therapeutics Foundation
- CHDI Foundation
- Pfizer Inc.
- AstraZeneca
- Bioline
- Bristol Myers-Squibb
- Cortex Pharmaceuticals, Inc.
- Dainippon Sumitomo Pharma
- Janssen
- Novartis
- Merck Serono
- Otsuka Pharmaceutical Co., Ltd.
- Roche
- Minster Pharmaceuticals plc
- Brain Imaging and Behavior
- Transdisciplinary Imaging Genetics Center (TIGC) [P20 RR020837-01]
- NIH/NINDS [R01 N5059873]
- Medco Health Solutions
- Baxter International Inc.
- NIH/NIA [P50-AG16574, U01AG06786, R01-AG11378, U01-24904]
- Nestle and Kenes International
- Merck Co.
- Avid Radiopharmaceuticals Inc.
- US Department of Defense
- Veterans Administration
- State of California
- Eli Lilly and Company
- Siemens AG
- Welch Allyn Inc.
- Indiana Economic Development Corporation [87884]
- Foundation for the NIH
- Alzheimer's Disease Genetics Consortium
- Alzheimer's Disease Neuroimaging Initiative (ADNI) [NIH U01 AG024904]
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Objectives: CSF levels of A beta(1-42), t-tau, and p-tau(181p) 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 (A beta(1-42), t-tau, p-tau(181p), p-tau(181p)/A beta(1-42), and t-tau/A beta(1-42)). 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 x 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. Neurology (R) 2011; 76:69-79
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