title: Performance of genotype imputation for low frequency and rare variants from the 1000 genomes.
abstract: Genotype imputation is now routinely applied in genome-wide association studies (GWAS) and meta-analyses. However, most of the imputations have been run using HapMap samples as reference, imputation of low frequency and rare variants (minor allele frequency (MAF) < 5%) are not systemically assessed. With the emergence of next-generation sequencing, large reference panels (such as the 1000 Genomes panel) are available to facilitate imputation of these variants. Therefore, in order to estimate the performance of low frequency and rare variants imputation, we imputed 153 individuals, each of whom had 3 different genotype array data including 317k, 610k and 1 million SNPs, to three different reference panels: the 1000 Genomes pilot March 2010 release (1KGpilot), the 1000 Genomes interim August 2010 release (1KGinterim), and the 1000 Genomes phase1 November 2010 and May 2011 release (1KGphase1) by using IMPUTE version 2. The differences between these three releases of the 1000 Genomes data are the sample size, ancestry diversity, number of variants and their frequency spectrum. We found that both reference panel and GWAS chip density affect the imputation of low frequency and rare variants. 1KGphase1 outperformed the other 2 panels, at higher concordance rate, higher proportion of well-imputed variants (info>0.4) and higher mean info score in each MAF bin. Similarly, 1M chip array outperformed 610K and 317K. However for very rare variants (MAF ≤ 0.3%), only 0-1% of the variants were well imputed. We conclude that the imputation of low frequency and rare variants improves with larger reference panels and higher density of genome-wide genotyping arrays. Yet, despite a large reference panel size and dense genotyping density, very rare variants remain difficult to impute.
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, and the Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China; Department of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Hou-Feng
authors.initials: HF
authors.lastname: Zheng
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, and the Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Rong
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, and the Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pulmonary, Critical Care Medicine, Peking University People's Hospital, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Han
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, and the Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Xing-Wei
authors.initials: XW
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, and the Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D005787:Gene Frequency; D015894:Genome, Human; D005838:Genotype; D060005:Genotyping Techniques; D016045:Human Genome Project; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide