RESUMO
The MHC/HLA region has been consistently associated with a large number of complex traits, including but not limited to, most immune-mediated ones. Efforts to pinpoint drivers of this commonly encountered association peak at the short arm of chromosome 6, however, have been challenging, owing to the high density of genes and the long and extended linkage disequilibrium that are characteristic of this region.The development of methods to impute classical HLA alleles and amino acids from SNP genotyping data has offered an important additional layer of information to the investigators seeking to fine map the signal in the region. As a result, imputation-aided association analyses are now typically employed to shed light on the relationship of this locus with disease susceptibility and response to drugs.In this chapter we discuss how the signal in the HLA region can be interrogated in practice, from performing the imputation to understanding its output and to incorporating it into downstream analysis. In addition, we recount some of the analytical approaches that are commonly used and suggest ways in which the findings from such imputation-aided analyses can be interpreted.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Antígenos HLA/genética , Alelos , Biologia Computacional/métodos , Suscetibilidade a Doenças , Estudos de Associação Genética/métodos , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Antígenos HLA/imunologia , HumanosRESUMO
Owing to the vast amount of alleles, high-resolution human leukocyte antigen (HLA) typing is expensive and time-consuming. Scientists have attempted to develop computational approaches to define HLA alleles with high confidence. We tested the reliability of HLA*IMP and SNP2HLA for imputing HLA-DRB1 alleles in a Finnish material (n=161). The per-individual success rates varied between 16.68% and 25.4% using both softwares. One of the most prominent example was HLA-DRB1*01:01 allele showing approximately a 30% success rate while being the most common wrongly imputed allele. In Finland, isolation and migration history have shaped the gene pool narrower showing HLA haplotype frequencies typical to the Finnish population when compared to Europeans. The imputation success for HLA-DRB1 alleles was very low pointing to the importance of population-specific reference material.