RESUMEN
The human leukocyte antigen (HLA) locus is associated with more complex diseases than any other locus in the human genome. In many diseases, HLA explains more heritability than all other known loci combined. In silico HLA imputation methods enable rapid and accurate estimation of HLA alleles in the millions of individuals that are already genotyped on microarrays. HLA imputation has been used to define causal variation in autoimmune diseases, such as type I diabetes, and in human immunodeficiency virus infection control. However, there are few guidelines on performing HLA imputation, association testing, and fine mapping. Here, we present a comprehensive tutorial to impute HLA alleles from genotype data. We provide detailed guidance on performing standard quality control measures for input genotyping data and describe options to impute HLA alleles and amino acids either locally or using the web-based Michigan Imputation Server, which hosts a multi-ancestry HLA imputation reference panel. We also offer best practice recommendations to conduct association tests to define the alleles, amino acids, and haplotypes that affect human traits. Along with the pipeline, we provide a step-by-step online guide with scripts and available software ( https://github.com/immunogenomics/HLA_analyses_tutorial ). This tutorial will be broadly applicable to large-scale genotyping data and will contribute to defining the role of HLA in human diseases across global populations.
Asunto(s)
Antígenos HLA , Antígenos de Histocompatibilidad Clase I , Humanos , Alelos , Antígenos HLA/genética , Genotipo , Haplotipos , Aminoácidos/genética , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma CompletoRESUMEN
Human leukocyte antigen (HLA) gene variants in the major histocompatibility complex (MHC) region are associated with numerous complex human diseases and quantitative traits. Previous phenome-wide association studies (PheWAS) for this region demonstrated that HLA association patterns to the phenome have both population-specific and population-shared components. We performed MHC PheWAS in the Korean population by analyzing associations between phenotypes and genetic variants in the MHC region using the Korea Biobank Array project data samples from the Korean Genome and Epidemiology Study cohorts. Using this single-population dataset, we curated and analyzed 82 phenotypes for 125 673 Korean individuals after imputing HLA using CookHLA, a recently developed imputation framework. More than one-third of these phenotypes showed significant associations, confirming 56 known associations and discovering 13 novel association signals that were not reported previously. In addition, we analyzed heritability explained by the variants in the MHC region and genetic correlations among phenotypes based on the MHC variants.
Asunto(s)
Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Humanos , Complejo Mayor de Histocompatibilidad/genética , Fenómica , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.
Asunto(s)
Variación Genética , Genética de Población , Infecciones por VIH/genética , Antígenos HLA/genética , Interacciones Huésped-Patógeno/genética , Mapeo Físico de Cromosoma , Alelos , Aminoácidos/genética , Frecuencia de los Genes/genética , VIH-1/genética , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Estándares de Referencia , Selección Genética , Carga ViralRESUMEN
The recent development of imputation methods enabled the prediction of human leukocyte antigen (HLA) alleles from intergenic SNP data, allowing studies to fine-map HLA for immune phenotypes. Here we report an accurate HLA imputation method, CookHLA, which has superior imputation accuracy compared to previous methods. CookHLA differs from other approaches in that it locally embeds prediction markers into highly polymorphic exons to account for exonic variability, and in that it adaptively learns the genetic map within MHC from the data to facilitate imputation. Our benchmarking with real datasets shows that our method achieves high imputation accuracy in a wide range of scenarios, including situations where the reference panel is small or ethnically unmatched.
Asunto(s)
Antígenos HLA/metabolismo , Alelos , Pueblo Asiatico , Diabetes Mellitus Tipo 1/genética , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Genotipo , Antígenos HLA/genética , Humanos , Modelos Teóricos , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
SUMMARY: Fine-mapping human leukocyte antigen (HLA) genes involved in disease susceptibility to individual alleles or amino acid residues has been challenging. Using information regarding HLA alleles obtained from HLA typing, HLA imputation or HLA inference, our software expands the alleles to amino acid sequences using the most recent IMGT/HLA database and prepares a dataset suitable for fine-mapping analysis. Our software also provides useful functionalities, such as various association tests, visualization tools and nomenclature conversion. AVAILABILITY AND IMPLEMENTATION: https://github.com/WansonChoi/HATK.
Asunto(s)
Antígenos HLA , Programas Informáticos , Alelos , Secuencia de Aminoácidos , Mapeo Cromosómico , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Prueba de Histocompatibilidad , HumanosRESUMEN
The Wellcome Trust Case Control Consortium (WTCCC) study was a large genome-wide association study that aimed to identify common variants associated with seven diseases. That study combined two control datasets (58C and UK Blood Services) as shared controls. Prior to using the combined controls, the WTCCC performed analyses to show that the genomic content of the control datasets was not significantly different. Recently, the analysis of human leukocyte antigen (HLA) genes has become prevalent due to the development of HLA imputation technology. In this project, we extended the between-control homogeneity analysis of the WTCCC to HLA. We imputed HLA information in the WTCCC control dataset and showed that the HLA content was not significantly different between the two control datasets, suggesting that the combined controls can be used as controls for HLA fine-mapping analysis based on HLA imputation.
