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

Webster, Jennifer and Reiman, Eric M. and Zismann, Victoria L. and Joshipura, Keta D. and Pearson, John V. and Hu-Lince, Diane and Huentelman, Matthew J. and Craig, David W. and Coon, Keith D. and Beach, Thomas and Rohrer, Kristen C. and Zhao, Alice S. and Leung, Doris and Bryden, Leslie and Marlowe, Lauren and Kaleem, Mona and Mastroeni, Diego and Grover, Andrew and Rogers, Joseph and Heun, Reinhard and Jessen, Frank and Kölsch, Heike and Heward, Christopher B. and Ravid, Rivka and Hutton, Michael L. and Melquist, Stacey and Petersen, Ron C. and Caselli, Richard J. and Papassotiropoulos, Andreas and Stephan, Dietrich A. and Hardy, John and Myers, Amanda. (2010) 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, Vol. 1, H. 1. pp. 19-30.

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Official URL: http://edoc.unibas.ch/dok/A6002590

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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 ?=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.
Faculties and Departments:03 Faculty of Medicine > Bereich Psychiatrie (Klinik) > Erwachsenenpsychiatrie UPK > Molekulare Neurowissenschaften (Papassotiropoulos)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Psychiatrie (Klinik) > Erwachsenenpsychiatrie UPK > Molekulare Neurowissenschaften (Papassotiropoulos)
05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Life Sciences Training Facility (Papassotiropoulos)
07 Faculty of Psychology > Departement Psychologie > Forschungsbereich Klinische Psychologie und Neurowissenschaften > Molecular Psychology (Papassotiropoulos)
UniBasel Contributors:Papassotiropoulos, Andreas
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:e-Century Publishing Corporation
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Sep 2015 14:31
Deposited On:24 May 2013 09:11

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