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Improved Imputation Accuracy of Rare and Low-Frequency Variants Using Population-Specific High-Coverage WGS-Based Imputation Reference Panel

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Improved Imputation Accuracy of Rare and Low-Frequency Variants Using Population-Specific High-Coverage WGS-Based Imputation Reference Panel Improved imputation accuracy of rare and low- frequency variants using population-specific high- coverage WGS-based imputation reference panel The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Mitt, Mario et al. “Improved Imputation Accuracy of Rare and Low- Frequency Variants Using Population-Specific High-Coverage WGS- Based Imputation Reference Panel.” European Journal of Human Genetics 25, 7 (April 2017): 869–876 © 2017 The Author(s) As Published http://dx.doi.org/10.1038/EJHG.2017.51 Publisher Nature Publishing Group Version Final published version Citable link http://hdl.handle.net/1721.1/116697 Terms of Use Creative Commons Attribution-NonCommercial 4.0 International Detailed Terms http://creativecommons.org/licenses/by-nc/4.0/ European Journal of Human Genetics (2017) 25, 869–876 Official journal of The European Society of Human Genetics www.nature.com/ejhg ARTICLE Improved imputation accuracy of rare and low-frequency variants using population-specific high-coverage WGS-based imputation reference panel Mario Mitt1,2,7, Mart Kals1,3,7, Kalle Pärn1,4,7, Stacey B Gabriel5, Eric S Lander5, Aarno Palotie4,5, Samuli Ripatti4, Andrew P Morris1,6, Andres Metspalu1,2, Tõnu Esko1,5, Reedik Mägi1,8 and Priit Palta*,1,4,8 Genetic imputation is a cost-efficient way to improve the power and resolution of genome-wide association (GWA) studies. Current publicly accessible imputation reference panels accurately predict genotypes for common variants with minor allele frequency (MAF) ≥ 5% and low-frequency variants (0.5 ≤ MAFo5%) across diverse populations, but the imputation of rare variation (MAFo0.5%) is still rather limited. In the current study, we evaluate imputation accuracy achieved with reference panels from diverse populations with a population-specific high-coverage (30 ×) whole-genome sequencing (WGS) based reference panel, comprising of 2244 Estonian individuals (0.25% of adult Estonians). Although the Estonian-specific panel contains fewer haplotypes and variants, the imputation confidence and accuracy of imputed low-frequency and rare variants was significantly higher. The results indicate the utility of population-specific reference panels for human genetic studies. European Journal of Human Genetics (2017) 25, 869–876; doi:10.1038/ejhg.2017.51; published online 12 April 2017 INTRODUCTION (HRC)20 contains even more individuals (N = 32 488, mostly with Genotype imputation is a method for statistically inferring untyped European ancestry) and should therefore enable better imputation of genotypes in a sample of partially genotyped individuals, based on a both low-frequency and rare variants in European samples. reference panel of individuals who have been more densely genotyped Recently, several studies have demonstrated that the use of or sequenced. Imputation methods attempt to identify haplotype population-specific IRPs can further improve the imputation accuracy sharing between individuals in the sample and in an imputation of common and low-frequency variants, and improve the imputation reference panel (IRP), and use this information to infer the alleles at of rarer variants in the relevant population.21–24 By using an IRP untyped loci in the sample.1 Imputation allows geneticists to study composed of related Dutch individuals, Deelan et al.23 showed that it variants that have not been directly genotyped in a sample and thereby is possible to substantially improve the completeness and accuracy of to increase power and resolution of genome-wide association studies imputation of rare variants into a set of Dutch individuals. Gudb- (GWAS). Imputation is particularly useful for combining association jartsson et al used long-range haplotype phasing in combination with results across studies that used different genotyping arrays2 and imputation to increase imputation accuracy for rare variants down to facilitate fine-mapping to localise association signals by considering MAF of 0.1% in the Icelandic population.22 Sidore et al.reported all genetic variants in a region. several variants associated with circulating lipid levels in Sardinians Publicly available IRPs from the International HapMap Project3,4 that were detected due to accurate imputation achieved by using a and 1000 Genomes Project (1000G)5 have been instrumental to the Sardinian WGS-based IRP; these authors showed that the variants discovery of thousands of loci affecting diseases and traits in individual would not have been identified if the analyses had been based on the GWAS and collaborative meta-analyses. The first wave of studies 1000G IRP.24 Similar results were obtained in the UK10K project, mostly used the HapMap II IRP, which used microarray-based where the British population-specific IRP combined with 1000G genotypes from 270 individuals at 3.1 million (M) variants.6–10 Later Project reference panel facilitated the discovery of several novel genetic studies used IRPs based on the 1000G project, which performed variants associated with medically relevant phenotypes.19,25,26 whole-genome sequencing (WGS) on a diverse set of populations, Studies have shown that the genetic structure of European countries with 2504 individuals and up to 84.4 M variants.11–16 Although the correlates closely with their geographic origin.27,28 The Estonian latter IRP allows robust imputation of common variants (minor allele population, being located in Northeast Europe, is genetically most frequency (MAF) ≥ 5%) and low-frequency variants (0.5 ≤ MAFo5%) similar to its neighbouring countries, including Finland, the North- 5 it has only limited imputation accuracy for rare (MAFo0.5%) western part of Russia, and other Baltic countries.28–30 Notwithstand- variants.17–19 A recent IRP from Haplotype Reference Consortium ing this overall genetic similarity, the Estonian population still has a 1Estonian Genome Center, University of Tartu, Tartu, Estonia; 2Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; 3Institute of Mathematics and Statistics, University of Tartu, Tartu, Estonia; 4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; 5Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; 6Department of Biostatistics, University of Liverpool, Liverpool, UK *Correspondence: Dr P Palta, Estonian Genome Center, University of Tartu, 23B Riia Street., 51010 Tartu, Estonia. Tel: +372 7375029; Fax: +372 7374060; E-mail: [email protected] 7These authors contributed equally to this work. 8These authors jointly supervised this work. Received 17 December 2016; revised 14 February 2017; accepted 25 February 2017; published online 12 April 2017 Imputation with population-specific reference MMittet al 870 substantial proportion of haplotypes that are not expected to be Multi-allelic SNVs were removed and we further excluded variants with call covered by the more diverse IRPs. Moreover, the population-specific rate o0.95, minor allele count ≤ 2, Hardy–Weinberg equilibrium test P- − differences are expected to increase as allele frequencies decrease. valueo1×10 6 and variants in low-complexity regions.35 fi In the current study, we first evaluated two most commonly used Genotype array data was ltered sample-wise by excluding on the basis of call o 4 ± phasing algorithms to create population-specific IRP based on high- rate ( 98%), extreme heterozygosity ( mean 3 SD), genotype and pheno- type sex discordance, cryptic relatedness (IBD420%) and outliers from the coverage (30 ×) WGS data from 2244 Estonian individuals. To impute fi European descent from the MDS plot in comparison with HapMap reference low-frequency and rare variants more accurately in a speci cpopula- samples. SNP quality filtering included call rate (o99%), MAF (o1%) and tion, one can take two approaches: (i) increase the size of IRPs extreme deviation from Hardy–Weinberg equilibrium (P-valueo1×10− 4). from diverse populations to capture more reference haplotypes or Non-autosomal SNPs were excluded from the analysis. (ii) employ population-specific IRPs. We assessed the utility of these approaches for improving imputation in Estonian samples by compar- Haplotype phasing ing the performance of (i) an Estonian-specific IRP, (ii) the commonly The EGCUT WGS data was phased with SHAPEIT2(ref. 36) (r837), using four used 1000G IRP, (iii) the much larger HRC IRP and (iv) combinations computer cores. Pre-phasing of genotype array data was made in similar of these panels. manner using SHAPEIT2 using four cores. As a separate test for pre-phasing accuracy, we used chromosome 20 sequence of 2244 full genomes, which fi MATERIALS AND METHODS were ltered beforehand to exclude any non-founder family members and individuals with a genome-wide PI_HAT value above 0.5 (2195 individuals Cohort description remained) when compared to other individuals in the data set. To assess the 2304 geographically distributed individuals (selected randomly by county of efficiency of various approaches to phasing of WGS data, we applied two birth) from the Estonian Biobank of the Estonian Genome Center, University different tools: SHAPEIT2(ref. 36) and Eagle2.37,38 Both programs were engaged of Tartu (EGCUT) were selected for WGS. EGCUT is a population-based with the default parameters with varying number of cores (1, 2, 4, 8, 16, 24 and biobank, containing almost 52 000 samples of the adult population (aged ≥ 18 32). To verify the phasing accuracy for other data sets, the 1000G data was years), which
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