Construction and benchmarking of a multi-ethnic reference panel for the imputation of HLA class I and II alleles

Abstract

Genotype imputation of the human leukocyte antigen (HLA) region is a cost-effective means to infer classical HLA alleles from inexpensive and dense SNP array data. In the research setting, imputation helps avoid costs for wet lab-based HLA typing and thus renders association analyses of the HLA in large cohorts feasible. Yet, most HLA imputation reference panels target Caucasian ethnicities and multi-ethnic panels are scarce. We compiled a high-quality multi-ethnic reference panel based on genotypes measured with Illumina’s Immunochip genotyping array and HLA types established using a high-resolution next generation sequencing approach. Our reference panel includes more than 1,300 samples from Germany, Malta, China, India, Iran, Japan and Korea and samples of African American ancestry for all classical HLA class I and II alleles including HLA-DRB3/4/5 . Applying extensive cross-validation, we benchmarked the imputation using the HLA imputation tool HIBAG, our multi-ethnic reference and an independent, previously published data set compiled of subpopulations of the 1000 Genomes project. We achieved average imputation accuracies higher than 0.924 for the commonly studied HLA-A , -B , -C , -DQB1 and -DRB1 genes across all ethnicities. We investigated allele-specific imputation challenges in regard to geographic origin of the samples using sensitivity and specificity measurements as well as allele frequencies and identified HLA alleles that are challenging to impute for each of the populations separately. In conclusion, our new multi-ethnic reference data set allows for high resolution HLA imputation of genotypes at all classical HLA class I and II genes including the HLA-DRB3/4/5 loci based on diverse ancestry populations.

Neolithic genomes reveal a distinct ancient HLA allele pool and population transformation in Europe

“…Only alleles that were consistently called by both methods were considered for the analysis. For comparing the ancient HLA allele pool with a representative modern allele pool, we used a cohort of 3,219 healthy northern German individuals and imputed HLA genotypes at 2 nd field level of resolution from high-density SNP data following an established procedure 66 .…”

Trans-ethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals shared but also ethnicity-specific disease associations

“…and -DPB1 at full context 4digit level using the IKMB reference published in Degenhardt et al 15 and the imputation tool HIBAG 24 .…”

“…Alleles were not excluded by setting a posterior probability threshold. However, we took the sensitivity and specificity measures we generated as previously reported (Degenhardt et al 15 ) into consideration during interpretation.…”

“…Recently, we created such a trans-ethnic HLA imputation reference panel including dense single nucleotide polymorphism (SNP) fine mapping data typed on Illumina's ImmunoChip, covering a large proportion of the HLA, within 8 populations of different ethnicities 15 . Here we report the first transethnic fine mapping study of the HLA in UC and some biological implications of the results.…”

Pervasive additive and non-additive effects within the HLA region contribute to disease risk in the UK Biobank

“…Chips (e.g. the Illumina MHC SNP Panel 12 ) and robust reference panels have been custom-built to study the region 13,14 , but there still exist well-studied alleles in the HLA region whose impact on disease are unknown. Thus, understanding the role of the HLA region is critical to assessing disease risk.…”