Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 22, Issue 10, Pages 1239-1242Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2013.308
Keywords
apolipoprotein E; APOE; epsilon alleles; GWAS; imputation
Funding
- NIH-NINDS [R01NS059727]
- Keane Stroke Genetics Research Fund
- Edward and Maybeth Sonn Research Fund
- University of Michigan General Clinical Research Center [M01 RR000042]
- National Center for Research Resources
- NIH-NINDS SPOTRIAS fellowship [P50NS061343]
- American Brain Foundation
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- BioClinica, Inc
- Biogen Idec Inc
- Bristol-Myers Squibb Company
- Eisai Inc
- Elan Pharmaceuticals, Inc
- Eli Lilly and Company
- F Hoffmann-La Roche Ltd
- Genentech, Inc
- GE Healthcare
- Irmogenetics, NV
- IXECO Ltd
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC
- Medpace, Inc
- Merck Co, Inc
- Meso Scale Diagnostics, LLC
- NeuroRx Research
- Novartis Pharmaceuticals Corporation
- Pfizer Inc
- Piramal Imaging
- Servier
- Synarc Inc
- Takeda Pharmaceutical Company
- Canadian Institutes of Health Research
- Foundation for the National Institutes of Health
- Northern California Institute for Research and Education
- NIH [P30 AG010129, K01 AG030514]
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Apolipoprotein E, encoded by APOE, is the main apoprotein for catabolism of chylomicrons and very low density lipoprotein. Two common single-nucleotide polymorphisms (SNPs) in APOE, rs429358 and rs7412, determine the three epsilon-alleles that are established genetic risk factors for late-onset Alzheimer's disease (AD), cerebral amyloid angiopathy, and intracerebral hemorrhage (ICH). These two SNPs are not present in most commercially available genome-wide genotyping arrays and cannot be inferred through imputation using HapMap reference panels. Therefore, these SNPs are often separately genotyped. Introduction of reference panels compiled from the 1000 Genomes project has made imputation of these variants possible. We compared the directly genotyped and imputed SNPs that define the APOE epsilon alleles to. determine the accuracy of imputation for inference of unobserved epsilon alleles. We utilized genome-wide genotype data obtained from two cohorts of ICH and AD constituting subjects of European ancestry. Our data suggest that imputation is highly accurate, yields an acceptable proportion of missing data that is non-differentially distributed across case and control groups, and generates comparable results to genotyped data for hypothesis testing. Further, we explored the effect of imputation algorithm parameters and demonstrated that customization of these parameters yields an improved balance between accuracy and missing data for inferred genotypes.
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