HLA imputation and its application to genetic and molecular fine-mapping of the MHC region in autoimmune diseases

Abstract

Variations of human leukocyte antigen (HLA) genes in the major histocompatibility complex region (MHC) significantly affect the risk of various diseases, especially autoimmune diseases. Fine-mapping of causal variants in this region was challenging due to the difficulty in sequencing and its inapplicability to large cohorts. Thus, HLA imputation, a method to infer HLA types from regional single nucleotide polymorphisms, has been developed and has successfully contributed to MHC fine-mapping of various diseases. Different HLA imputation methods have been developed, each with its own advantages, and recent methods have been improved in terms of accuracy and computational performance. Additionally, advances in HLA reference panels by next-generation sequencing technologies have enabled higher resolution and a more reliable imputation, allowing a finer-grained evaluation of the association between sequence variations and disease risk. Risk-associated variants in the MHC region would affect disease susceptibility through complicated mechanisms including alterations in peripheral responses and central thymic selection of T cells. The cooperation of reliable HLA imputation methods, informative fine-mapping, and experimental validation of the functional significance of MHC variations would be essential for further understanding of the role of the MHC in the immunopathology of autoimmune diseases.

Exploring the causal role of the immune response to varicella-zoster virus on multiple traits: a phenome-wide Mendelian randomization study

“…It would be advisable to investigate this separately in future MR studies. Moreover, as MHC IVs can potentially have an impact on MR analysis, imputing the region using specialist software would enhance accuracy and resolution for causal findings [ 56 ].…”

How genetic risk contributes to autoimmune liver disease

“…Subsequent GWAS and genome-wide meta-analyses (GWMA) used HLA imputation methods to investigate a variety of HLA alleles as possible susceptibility alleles. HLA imputation is a method of deriving HLA types for patients and controls in GWAS studies by imputing (predicting) genotypes of HLA genes using regional SNPs and a SNP-HLA-allele reference panel for imputation [ 31 ]. In a first GWAS for AIH [ 27 ], involving 649 adult AIH patients and 13,436 controls, followed by replication in 451 patients and 4103 controls, the strongest genome-wide significant ( P < 5 × 10 −8 ) association signal for SNP rs2187668 was found at 6p21.32 , and HLA imputation assigned the SNP signals to HLA-DRB1*03:01 , which is considered the primary AIH susceptibility allele (Table 1 ); HLA-DRB1*04:01 was identified as another independent (i.e., secondary) AIH susceptibility allele by conditional forward stepwise logistic regression analysis [ 32 ].…”

“…For this reason, I have listed in Table 1 only statistically independent and genome-wide significant HLA susceptibility alleles (cluster representatives) that are also genome-wide significant after conditioning regression analysis. The identification (fine-mapping) of a complete set of potentially “causal” HLA alleles in the overall context of all class I and I genes requires the use of high-quality multi-ethnic reference panels from different genetic backgrounds [ 46 , 47 ], highly accurate HLA type imputation algorithms [ 31 ], the study of non-additive and interaction effects [ 48 ], inclusion of amino acid alleles composing HLA alleles [ 49 ], and functional fine-mapping approaches [ 50 – 52 ]. Future HLA fine-mapping studies for AIH, PBC, and PSC therefore have the potential to further refine these signals from previous GWAS and HLA imputation studies.…”

Genetics and functional genetics of autoimmune diseases

“…Human leukocyte antigen (HLA) genes at 6p23 explain significant proportions of genetic risk of autoimmune diseases. Naito et al [7] presents current fine-mapping efforts to dissect causal HLA variants of autoimmune diseases. Then, Ha et al [8], Padyukov et al [9], Kim et al [10], and Márquez et al [11] summarize recent achievements in genetics of four major autoimmune diseases of systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes, respectively.…”