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P2‐018: Association study of recently reported AD risk variants with cerebrospinal fluid AD biomarker levels
Author(s) -
Bailey Matthew,
Kauwe John,
Cruchaga Carlos,
McKean David,
Mayo Kevin,
Bertelsen Sarah,
Hinrichs Tony,
Fagan Anne,
Holtzman David,
Goate Alison
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.908
Subject(s) - single nucleotide polymorphism , snp , genome wide association study , genotype , medicine , disease , covariate , apolipoprotein e , biomarker , oncology , genetic association , cerebrospinal fluid , genetics , biology , bioinformatics , gene , statistics , mathematics
Background:Two large scale GWAS of late onset Alzheimer’s disease have identified several novel risk loci (Naj et al in press, Hollingworth et al in press). While significant and replicable association for these variants has been shown, the biological mechanisms for risk are still largely unknown. The purpose of this study is to evaluate the SNPs from these recent reports for association with cerebrospinal fluid biomarkers for AD to provide insight into possible biological mechanisms by which these SNPs influence Alzheimer’s disease. Methods: CSF Aß42 and tau levels were measured in 957 samples including 356 samples the Knight ADRC, 391 from the Alzheimer’s Disease Neuroimaging Initiative and 210 from the University of Washington. Analyses were restricted to individuals with European American Ancestry. The samples were genotyped using Illumina BeadChips. Approximately 275,000 SNPs were directly genotyped in all series. CSFAß42 levels are not normally distributed required analysis in each series separately. Analyses were performed using linear regression with age, principle components from stratification analyses and/or APOE genotype as covariates. Empirical P-values for each SNP were generated using ten million permutations. Metaanalysis of the three series was performed using METAL. CSF tau levels were standardized to a mean of zero in each series. The combined sample was then analyzed using linear regression including age, principal components from EigenStrat analysis and series as covariates. Results:We had genotypes for 5 of the 13 SNPs reported in the two studies. We failed to detect significant association with CSFAß42, tau or ptau levels in our sample of 850 individuals. Power to detect a 5% difference between the genotype groups assuming an additive model with Alpha 1⁄4 0.05 and a minor allele frequency of 0.10 is 0.97. Conclusions: Our study was designed to detect associations between specific biomarkers and biological mechanisms. This study does not address replication o1⁄4 of case-control associations. Given our statistical power it is unlikely that there are strong additive effects between these five variants and CSF biomarker levels. We will soon obtain genotypes for the remaining SNPs and analyses of the complete set of variants will be reported at the meeting.