Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from Meta-analysis

International Journal of Molecular Epidemiology and Genetics

Lauren Marlowe¹  Mona Kaleem¹  Joseph Rogers¹  Frank Jessen¹  Rivka Ravid¹  Amanda Myers¹  Reinhard Heun¹  Ron C Petersen¹  Dietrich A Stephan¹  Michael L Hutton¹  Heike Kölsch¹  Keta D Joshipura¹  Andreas Papassotiropoulos¹  Richard J Caselli¹  John Hardy¹  Diane Hu-Lince¹  Jennifer Webster¹  Thomas Beach¹  Stacey Melquist¹  Christopher B Heward¹  Andrew Grover¹  Eric M Reiman¹  Kristen C Rohrer¹  Keith D Coon¹  Alice S Zhao¹  Doris Leung¹  Leslie Bryden¹  Diego Mastroeni¹  Matthew J Huentelman¹  Victoria L Zismann¹  David W Craig¹  John v Pearson¹ 

关键词: Late-onset Alzheimer disease;    single nucleotide polymorphism;    genome-wide association study;    meta-analysis;    ACE;   

DOI  :  

学科分类：流行病学

来源: e-Century Publishing Corporation

【 摘 要 】

For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1^st, 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 “top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected p-value=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (p-value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies.

【 授权许可】

Unknown