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.