期刊
GENETIC EPIDEMIOLOGY
卷 36, 期 2, 页码 107-117出版社
WILEY
DOI: 10.1002/gepi.21603
关键词
genotype imputation; Metabochip; internal reference; African Americans; rare variants
资金
- National Human Genome Research Institute (NHGRI)
- National Heart, Lung, and Blood Institute
- NIH
- U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]
- [5 UC2 HL102924-02]
- [3-R01-CA082659-11S1]
- [R01HG006292]
- [U01HG004803 (CALiCo)]
- [U01HG004798 (EAGLE)]
- [U01HG004802 (MEC)]
- [U01HG004790 (WHI)]
- [U01HG004801]
- Div Of Information & Intelligent Systems
- Direct For Computer & Info Scie & Enginr [812464] Funding Source: National Science Foundation
Genetic imputation has become standard practice in modern genetic studies. However, several important issues have not been adequately addressed including the utility of study-specific reference, performance in admixed populations, and quality for less common (minor allele frequency [MAF] 0.005-0.05) and rare (MAF < 0.005) variants. These issues only recently became addressable with genome-wide association studies (GWAS) follow-up studies using dense genotyping or sequencing in large samples of non-European individuals. In this work, we constructed a study-specific reference panel of 3,924 haplotypes using African Americans in the Women's Health Initiative (WHI) genotyped on both the Metabochip and the Affymetrix 6.0 GWAS platform. We used this reference panel to impute into 6,459 WHI SNP Health Association Resource (SHARe) study subjects with only GWAS genotypes. Our analysis confirmed the imputation quality metric Rsq (estimated r(2), specific to each SNP) as an effective post-imputation filter. We recommend different Rsq thresholds for different MAF categories such that the average (across SNPs) Rsq is above the desired dosage r2 (squared Pearson correlation between imputed and experimental genotypes). With a desired dosage r(2) of 80%, 99.9% (97.5%, 83.6%, 52.0%, 20.5%) of SNPs with MAF > 0.05 (0.03-0.05, 0.01-0.03, 0.005-0.01, and 0.001-0.005) passed the post-imputation filter. The average dosage r(2) for these SNPs is 94.7%, 92.1%, 89.0%, 83.1%, and 79.7%, respectively. These results suggest that for African Americans imputation of Metabochip SNPs from GWAS data, including low frequency SNPs with MAF 0.005-0.05, is feasible and worthwhile for power increase in downstream association analysis provided a sizable reference panel is available. Genet. Epidemiol. 36: 107-117, 2012. (C) 2012 Wiley Periodicals, Inc.
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