IJMEG Copyright © 2010-present. All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Mol Epidemiol Genet 2010;1(1):19-30.

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

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. Roher, 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. Caselli6, Andreas
Papassotiropoulos, Dietrich A. Stephan, John Hardy5, Amanda Myers

Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ85004, USA
Banner Alzheimer’s Institute, Phoenix, AZ85006, USA
Department of Psychiatry, University of Arizona, Tucson, AZ85724, USA
Department of Psychiatry and Behavioral Sciences, University of Miami, Miller School of Medicine, Miami, FL33136, USA
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD20892, USA
Arizona Alzheimer’s Consortium, Phoenix AZ85006, USA
Division of Thoracic Oncology Research, St. Joseph's Hospital and Medical Center, Phoenix, AZ85013, USA
Sun Health Research Institute, Sun City, AZ85351, USA
Department of Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
Kronos Science Laboratory, Phoenix, AZ85016, USA
Netherlands Institute for Neurosciences, Dutch Royal Academy of Arts and Sciences, Meibergdreef 47 AB Amsterdam, The
Department of Neuroscience, Mayo Clinic, Jacksonville, FL32224, USA
Department of Neurology, Mayo Clinic, Rochester, MN55905, USA
Department of Neurology, Mayo Clinic, Scottsdale, AZ85259, USA
Department of Psychology, Arizona State University, Tempe, AZ85281, USA
Division of Molecular Psychology and Life Sciences Training Facility, Biozentrum, University of Basel, Switzerland
Reta Lila Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London
WC1N3BG, England

Received July 20, 2009; accepted September 28, 2009; available online October 5, 2009

Abstract: For late onset Alzheimer’s disease (AD), 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.  AD research
has the advantage of a continuously updated meta-analysis of candidate gene association studies in the AlzGene database.  
The top 30 AlzGene loci on May 1st, 2007 were investigated in our whole genome association data set consisting of 1411
subjects 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 AD 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 along with a discussion of the statistical limitations of multiple
test corrections in whole genome studies.(IJMEG907003).

Key words: Late-onset Alzheimer disease, single nucleotide polymorphism, genome-wide association study, meta-analysis,

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Address all correspondence to:
John Hardy, PhD
17Reta Lila Weston Laboratories
Department of Molecular Neuroscience
Institute of Neurology, Queen Square
London WC1N3BG, England.