Increasing accuracy of HLA imputation by a population-specific reference panel in a FinnGen biobank cohort.

The HLA genes, the most polymorphic genes in the human genome, constitute the strongest single genetic susceptibility factor for autoimmune diseases, transplantation alloimmunity and infections. HLA imputation via statistical inference of alleles based on single-nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) with alleles is a powerful first-step screening tool. Due to different LD structures between populations, the accuracy of HLA imputation may benefit from matching the imputation reference with the study population. To evaluate the potential advantage of using population-specific reference in HLA imputation, we constructed an HLA reference panel consisting of 1150 Finns with 5365 major histocompatibility complex region SNPs consistent between genome builds. We evaluated the accuracy of the panel against a European panel in an independent test set of 213 Finnish subjects. We show that the Finnish panel yields a lower imputation error rate (1.24% versus 1.79%). More than 30% of imputation errors occurred in haplotypes enriched in Finland. The frequencies of imputed HLA alleles were highly correlated with clinical-grade HLA allele frequencies and allowed accurate replication of established HLA-disease associations in ∼102 000 biobank participants. The results show that a population-specific reference increases imputation accuracy in a relatively isolated population within Europe and can be successfully applied to biobank-scale genome data collections.