Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from Meta-analysis.
Year: 2010
Type: article
Study design: Observational Study
Abstract: 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.
Source: PubMed Central
Authors: Jennifer Webster, Eric M Reiman, Victoria L Zismann, Keta D Joshipura, John V Pearson, Diane Hu-Lince, Matthew J Huentelman, David W Craig, Keith D Coon, Thomas Beach, Kristen C Rohrer, Alice S Zhao, Doris Leung, Leslie Bryden, Lauren Marlowe, Mona Kaleem, Diego Mastroeni, Andrew Grover, Joseph Rogers, Reinhard Heun, Frank Jessen, Heike Kölsch, Christopher B Heward, Rivka Ravid, Michael L Hutton, Stacey Melquist, Ron C Petersen, Richard J Caselli, Andreas Papassotiropoulos, Dietrich A Stephan, John Hardy, Amanda Myers
Institutions: Translational Genomics Research Institute, St. Joseph's Hospital and Medical Center, Arizona Alzheimer’s Consortium, National Institutes of Health, Banner Sun Health Research Institute, University of Bonn, Netherlands Institute for Neuroscience, Mayo Clinic, University of Basel, University College London, University of Miami
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Neurogenomics of Alzheimer's Disease and Aging, ALZHEIMER'S DISEASE RESEARCH CENTER, Neurofibrillary Tangle-Induced Dementia in AD, Microarray Center for Research on the Nervous System, Neurobiology of Alzheimer's Disease and Aging, STANFORD ALZHEIMER'S DISEASE CORE CENTER, National Alzheimer's Coordinating Center, Genetic Variation in KIBRA and its role in Human Episodic Memory, UCLA Alzheimer's Disease Research Center, ALZHEIMER'S DISEASE RESEARCH CENTER, Rush Alzheimer's Disease Core Center, Alzheimer's Disease Research Center - Overall, Brain Aging & Gene Expression Patterns Using Microarrays, Florida Alzheimer's Disease Research, Alzheimer's Disease Research Center, Alzheimer Disease Research Center, Michigan Alzheimer's Disease Research Center, Arizona Alzheimer's Disease Core Center, Johns Hopkins Alzheimer's Disease Research Center, Boston University Alzheimer's Disease Center, Alzheimer's Disease Research Center, Massachusetts Alzheimer's Disease Research Center, Emory Alzheimer's Disease Center, The Genetics of Parkinsonism, Conte Centers for the Neuroscience of Depression, Mayo Alzheimer's Disease Research Center
OpenAlex ID: W1500736474