Advantages of genotype imputation with ethnically matched reference panel for rare variant association analyses

Genotype imputation has become a standard technique prior genome-wide association studies (GWASs). For common and low-frequency variants, genotype imputation can be performed sufficiently accurately with publicly available and ethnically heterogeneous imputation reference panels like 1000 Genomes Project (1000G) and Haplotype Reference Consortium. However, the imputation of rare variants has been shown to be significantly more accurate when ethnically matched reference panel is used. Even more, greater genetic similarity between reference panel and target samples facilitates the detection of rare (or even population-specific) causal variants. Notwithstanding, the genome-wide downstream consequences and differences of using ethnically mixed and matched reference panels have not been yet comprehensively explored. We determined and quantified these differences by performing several comparative evaluations of the discovery-driven analysis scenarios. A variant-wise GWAS was performed on seven complex diseases and body mass index by using genome-wide genotype data of ~37,000 Estonians imputed with ethnically mixed 1000G and ethnically matched imputation reference panels. Although several previously reported common (minor allele frequency; MAF > 5%) variant associations were replicated in both imputed datasets, no major differences were observed among the genome-wide significant findings or in the fine-mapping effort. In the analysis of rare (MAF