APOE is not associated with Alzheimer disease: a cautionary tale of genotype imputation.
- Authors
- Beecham, Gary W; Martin, Eden R; Gilbert, John R; Haines, Jonathan L; Pericak-Vance, Margaret A
- Year
- 2010
- Journal
- Annals of human genetics
- PMID
- 20529013
- DOI
- 10.1111/j.1469-1809.2010.00573.x
- PMCID
- PMC2934779
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.
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| Illuminating the full spectrum of APOE variation. | Hegele RA | — | 2023 | → |
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| Assessing accuracy of genotype imputation in American Indians. | Malhotra A et al. | — | 2014 | → |
| Value of Mendelian laws of segregation in families: data quality control, imputation, and beyond. | Blue EM et al. | — | 2014 | → |
| Effects of APOA5 -1131T>C (rs662799) on fasting plasma lipids and risk of metabolic syndrome: evidence from a case-control study in China and a meta-analysis. | Xu C et al. | — | 2013 | → |
| Imputation across genotyping arrays for genome-wide association studies: assessment of bias and a correction strategy. | Johnson EO et al. | — | 2013 | → |
| Artifact due to differential error when cases and controls are imputed from different platforms. | Sinnott JA et al. | — | 2012 | → |
| Assessment of genotype imputation performance using 1000 Genomes in African American studies. | Hancock DB et al. | — | 2012 | → |
| High density GWAS for LDL cholesterol in African Americans using electronic medical records reveals a strong protective variant in APOE. | Rasmussen-Torvik LJ et al. | — | 2012 | → |
| Assessing the impact of non-differential genotyping errors on rare variant tests of association. | Powers S et al. | — | 2011 | → |