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APOE is not Associated with Alzheimer Disease: a Cautionary tale of Genotype Imputation

APOE is not Associated with Alzheimer Disease: a Cautionary tale of Genotype Imputation With the advent of publicly available genome‐wide genotyping data, the use of genotype imputation methods is becoming increasingly common. These methods are of particular use in joint analyses, where data from different genotyping platforms are imputed to a reference set and combined in a single analysis. We show here that such an analysis can miss strong genetic association signals, such as that of the apolipoprotein‐e gene in late‐onset Alzheimer disease. This can occur in regions of weak to moderate LD; unobserved SNPs are not imputed with confidence so there is no consensus SNP set on which to perform association tests. Both IMPUTE and Mach software are tested, with similar results. Additionally, we show that a meta‐analysis that properly accounts for the genotype uncertainty can recover association signals that were lost under a joint analysis. This shows that joint analyses of imputed genotypes, particularly failure to replicate strong signals, should be considered critically and examined on a case‐by‐case basis. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Human Genetics Wiley

APOE is not Associated with Alzheimer Disease: a Cautionary tale of Genotype Imputation

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References (27)

Publisher
Wiley
Copyright
Copyright © 2010 Wiley Subscription Services
ISSN
0003-4800
eISSN
1469-1809
DOI
10.1111/j.1469-1809.2010.00573.x
pmid
20529013
Publisher site
See Article on Publisher Site

Abstract

With the advent of publicly available genome‐wide genotyping data, the use of genotype imputation methods is becoming increasingly common. These methods are of particular use in joint analyses, where data from different genotyping platforms are imputed to a reference set and combined in a single analysis. We show here that such an analysis can miss strong genetic association signals, such as that of the apolipoprotein‐e gene in late‐onset Alzheimer disease. This can occur in regions of weak to moderate LD; unobserved SNPs are not imputed with confidence so there is no consensus SNP set on which to perform association tests. Both IMPUTE and Mach software are tested, with similar results. Additionally, we show that a meta‐analysis that properly accounts for the genotype uncertainty can recover association signals that were lost under a joint analysis. This shows that joint analyses of imputed genotypes, particularly failure to replicate strong signals, should be considered critically and examined on a case‐by‐case basis.

Journal

Annals of Human GeneticsWiley

Published: Jan 1, 2010

Keywords: ; ; ;

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