title: On combining reference data to improve imputation accuracy.
abstract: Genotype imputation is an important tool in human genetics studies, which uses reference sets with known genotypes and prior knowledge on linkage disequilibrium and recombination rates to infer un-typed alleles for human genetic variations at a low cost. The reference sets used by current imputation approaches are based on HapMap data, and/or based on recently available next-generation sequencing (NGS) data such as data generated by the 1000 Genomes Project. However, with different coverage and call rates for different NGS data sets, how to integrate NGS data sets of different accuracy as well as previously available reference data as references in imputation is not an easy task and has not been systematically investigated. In this study, we performed a comprehensive assessment of three strategies on using NGS data and previously available reference data in genotype imputation for both simulated data and empirical data, in order to obtain guidelines for optimal reference set construction. Briefly, we considered three strategies: strategy 1 uses one NGS data as a reference; strategy 2 imputes samples by using multiple individual data sets of different accuracy as independent references and then combines the imputed samples with samples based on the high accuracy reference selected when overlapping occurs; and strategy 3 combines multiple available data sets as a single reference after imputing each other. We used three software (MACH, IMPUTE2 and BEAGLE) for assessing the performances of these three strategies. Our results show that strategy 2 and strategy 3 have higher imputation accuracy than strategy 1. Particularly, strategy 2 is the best strategy across all the conditions that we have investigated, producing the best accuracy of imputation for rare variant. Our study is helpful in guiding application of imputation methods in next generation association analyses.
authors: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, United States of America.
authors: Jun
authors: J
authors: Chen
authors: Ji-Gang
authors: JG
authors: Zhang
authors: Jian
authors: J
authors: Li
authors: Yu-Fang
authors: YF
authors: Pei
authors: Hong-Wen
authors: HW
authors: Deng
mesh_terms: D000483:Alleles; D000818:Animals; D003198:Computer Simulation; D005787:Gene Frequency; D014644:Genetic Variation; D023281:Genomics; D005838:Genotype; D060148:HapMap Project; D006801:Humans; D020407:Internet; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D015203:Reproducibility of Results; D012984:Software
references: Am J Hum Genet. 2007 Nov;81(5):1084-97
references: 17924348
references: PLoS One. 2008;3(10):e3551
references: 18958166
references: Science. 2007 Jun 1;316(5829):1341-5
references: 17463248
references: Nat Rev Genet. 2010 Jan;11(1):31-46
references: 19997069
references: Am J Hum Genet. 2001 Apr;68(4):978-89
references: 11254454
references: Bioinformatics. 2011 Aug 15;27(16):2304-5
references: 21653516
references: Genet Epidemiol. 2010 Dec;34(8):816-34
references: 21058334
references: Genome Res. 2011 Jun;21(6):940-51
references: 21460063
references: Nat Rev Genet. 2010 Jul;11(7):499-511
references: 20517342
references: Nature. 2007 Oct 18;449(7164):851-61
references: 17943122
references: Am J Hum Genet. 2003 Nov;73(5):1162-9
references: 14574645
references: Nat Rev Genet. 2011 Sep 16;12(10):703-14
references: 21921926
references: Lancet. 2008 Feb 9;371(9611):483-91
references: 18262040
references: PLoS Genet. 2007 Jul;3(7):e114
references: 17676998
references: Nat Genet. 2011 Dec 27;44(1):6-7
references: 22200770
references: Mol Biol Evol. 2008 Jan;25(1):199-206
references: 17981928
references: PLoS One. 2011;6(9):e24945
references: 21949800
references: Nature. 2010 Oct 28;467(7319):1061-73
references: 20981092
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D613-9
references: 19906737
references: Am J Hum Genet. 2006 Apr;78(4):629-44
references: 16532393
references: Nat Genet. 2010 Jun;42(6):495-7
references: 20453840
references: Genetics. 2009 May;182(1):295-301
references: 19293142
references: PLoS Genet. 2009 May;5(5):e1000477
references: 19492015
references: Am J Hum Genet. 2010 Apr 9;86(4):526-39
references: 20303063
references: Genome Res. 2010 Mar;20(3):291-300
references: 20067940
references: Nat Genet. 2010 May;42(5):436-40
references: 20418889
references: Nat Genet. 2007 Jul;39(7):906-13
references: 17572673
references: Genome Res. 2009 Feb;19(2):336-46
references: 19056694