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

By Mart Kals, Tiit Nikopensius, Kristi Läll, Kalle Pärn, Timo Tõnis Sikka, Jaana Suvisaari, Veikko Salomaa, Samuli Ripatti, Aarno Palotie, Andres Metspalu, Tõnu Esko, Priit Palta, Reedik Mägi

Posted 16 Mar 2019
bioRxiv DOI: 10.1101/579201

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 < 1%) coding variants, 46 significantly associated genes were identified in the ethnically matched imputed data as compared to four genes in the 1000G panel based imputed data. All resulting genes were consequently studied in the UK Biobank data. These associated genes provide an example of how rare variants can be efficiently analysed to discover novel, potentially functional genetic variants in relevant phenotypes. Furthermore, our work serves as proof of a cost-efficient study design, demonstrating that the usage of ethnically matched imputation reference panels can enable improved imputation of rare variants, facilitating novel high-confidence findings in rare variant GWAS scans.

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