Dataset Information

Comparison of HLA allelic imputation programs.

ABSTRACT: Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.

SUBMITTER: Karnes JH

PROVIDER: S-EPMC5312875 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Comparison of HLA allelic imputation programs.

Karnes Jason H JH Shaffer Christian M CM Bastarache Lisa L Gaudieri Silvana S Glazer Andrew M AM Steiner Heidi E HE Mosley Jonathan D JD Mallal Simon S Denny Joshua C JC Phillips Elizabeth J EJ Roden Dan M DM

PloS one 20170216 2

Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database c ...[more]

PMID: 28207879

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Project description:This study investigated using imputed genotypes from non-genotyped animals which were not in the pedigree for the purpose of genetic selection and improving genetic gain for economically relevant traits. Simulations were used to mimic a 3-breed crossbreeding system that resembled a modern swine breeding scheme. The simulation consisted of three purebred (PB) breeds A, B, and C each with 25 and 425 mating males and females, respectively. Males from A and females from B were crossed to produce AB females (n = 1,000), which were crossed with males from C to produce crossbreds (CB; n = 10,000). The genome consisted of three chromosomes with 300 quantitative trait loci and ~9,000 markers. Lowly heritable reproductive traits were simulated for A, B, and AB (h2 = 0.2, 0.2, and 0.15, respectively), whereas a moderately heritable carcass trait was simulated for C (h2 = 0.4). Genetic correlations between reproductive traits in A, B, and AB were moderate (rg = 0.65). The goal trait of the breeding program was AB performance. Selection was practiced for four generations where AB and CB animals were first produced in generations 1 and 2, respectively. Non-genotyped AB dams were imputed using FImpute beginning in generation 2. Genotypes of PB and CB were used for imputation. Imputation strategies differed by three factors: 1) AB progeny genotyped per generation (2, 3, 4, or 6), 2) known or unknown mates of AB dams, and 3) genotyping rate of females from breeds A and B (0% or 100%). PB selection candidates from A and B were selected using estimated breeding values for AB performance, whereas candidates from C were selected by phenotype. Response to selection using imputed genotypes of non-genotyped animals was then compared to the scenarios where true AB genotypes (trueGeno) or no AB genotypes/phenotypes (noGeno) were used in genetic evaluations. The simulation was replicated 20 times. The average increase in genotype concordance between unknown and known sire imputation strategies was 0.22. Genotype concordance increased as the number of genotyped CB increased with little additional gain beyond 9 progeny. When mates of AB were known and more than 4 progeny were genotyped per generation, the phenotypic response in AB did not differ (P > 0.05) from trueGeno yet was greater (P < 0.05) than noGeno. Imputed genotypes of non-genotyped animals can be used to increase performance when 4 or more progeny are genotyped and sire pedigrees of CB animals are known.

Dataset Information

Comparison of HLA allelic imputation programs.

Publications

Comparison of HLA allelic imputation programs.

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