The hazards of genotype imputation in chromosomal regions under selection: A case study using the Lactase gene region.

Abstract

Although imputation of missing SNP results has been widely used in genetic studies,claims about the quality and usefulness of imputation have outnumbered the few studies that havequestioned its limitations.But it is becoming clear that these limitations are real-for example,disease association signals can be missedin regions of LD breakdown.Here, as a case study, using the chromosomal region of the well-known lactase gene, LCT, we address the issue of imputation in the context of variants that have become frequent in a limited number of modern population groups only recently, due to selection.We study SNPs in a 500 bp region covering the enhancer of LCT,and compare imputed genotypes with directly genotyped data.We examine the haplotype pairs of all individuals with discrepant and missing genotypes.We highlight the nonrandom nature of the allelic errorsand showthat most incorrect imputations and missing data result fromlonghaplotypes that are evolutionarily closely related to those carrying the derived alleles, while some relate torare andrecombinant haplotypes.We conclude thatbiasofincorrectlyimputed and missing genotypescan decrease the accuracy of imputed resultssubstantially.