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Hum Mol Genet. 2019 Jun 15;28(12):2078-2092. doi: 10.1093/hmg/ddy443.

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

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Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Department of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Division of Gastroenterology, Mater Dei Hospital, Msida MSD, Malta.
Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Biobank PopGen and Institute of Epidemiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Department of Epidemiology, University Medical Center Groningen, RB Groningen, The Netherlands.
Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.
Department of Medicine, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.
Department of Genetics, University of Delhi South Campus, New Delhi, India.
Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan.
Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Tokyo, Japan.
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Montreal Heart Institute, Research Center, Montréal, Québec, Canada.
Université de Montréal Department of Medicine, Montréal, Québec, Canada.
Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön, Germany.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Medicine, Rutgers Robert Wood Johnson Medical School and Department of Genetics, Rutgers University, New Brunswick and Piscataway, NJ, USA.


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.

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