Imputation of missing genotypes within LD-blocks relying on the basic coalescent and beyond: consideration of population growth and structure

Abstract

Background: Genotypes not directly measured in genetic studies are often imputed to improve statistical power and to increase mapping resolution. The accuracy of standard imputation techniques strongly depends on the similarity of linkage disequilibrium (LD) patterns in the study and reference populations. Here we develop a novel approach for genotype imputation in low-recombination regions that relies on the coalescent and permits to explicitly account for population demographic factors. To test the new method, study and reference haplotypes were simulated and gene trees were inferred under the basic coalescent and also considering population growth and structure. The reference haplotypes that first coalesced with study haplotypes were used as templates for genotype imputation. Computer simulations were complemented with the analysis of real data. Genotype concordance rates were used to compare the accuracies of coalescent-based and standard (IMPUTE2) imputation.

Results: Simulations revealed that, in LD-blocks, imputation accuracy relying on the basic coalescent was higher and less variable than with IMPUTE2. Explicit consideration of population growth and structure, even if present, did not practically improve accuracy. The advantage of coalescent-based over standard imputation increased with the minor allele frequency and it decreased with population stratification. Results based on real data indicated that, even in low-recombination regions, further research is needed to incorporate recombination in coalescence inference, in particular for studies with genetically diverse and admixed individuals.

Conclusions: To exploit the full potential of coalescent-based methods for the imputation of missing genotypes in genetic studies, further methodological research is needed to reduce computer time, to take into account recombination, and to implement these methods in user-friendly computer programs. Here we provide reproducible code which takes advantage of publicly available software to facilitate further developments in the field.

Keywords: Coalescent theory; Genotype imputation; Imputation accuracy; Linkage disequilibrium; Population growth; Population structure.

Fig. 1

Overview of conducted simulations and proposed algorithm for coalescent-based genotype imputation

Fig. 2

a-d Accuracy of imputation relying on the coalescent (black) and with IMPUTE2 (gray) represented by mean concordance rates with the corresponding 95% confidence intervals (shown as error bars). a 1000 haplotypes were simulated under the basic coalescent. Genotypes were imputed based on the basic coalescent and with IMPUTE2 without recombination. Results are presented for all variants and stratified by minor allele frequency. b Different total numbers of haplotypes were simulated under the basic coalescent. Genotypes were imputed based on the basic coalescent and with IMPUTE2 without recombination. c Haplotypes were simulated under the basic coalescent extended to accommodate different exponential growth rates (α). Genotypes were imputed based on the coalescent with growth, and with IMPUTE2 without recombination. d Haplotypes were simulated under the coalescent extended to consider different numbers of subpopulations (β). Genotypes were imputed based on the coalescent with population structure and with IMPUTE2 without recombination