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 Netherlands 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, ACE
Address all correspondence to: John Hardy, PhD 17Reta Lila Weston Laboratories Department of Molecular Neuroscience Institute of Neurology, Queen Square London WC1N3BG, England. E-mail: email@example.com