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Improved imputation quality of low-frequency and rare variants in European samples using the ‘Genome of The Netherlands'

Journal article published in 2014 by Elisabeth M. van Leeuwen, Jessica van Setten, Mannis van Oven, Leonard H. van den Berg, K. Joeri van der Velde, Barbera D. C. van Schaik, Gertjan B. van Ommen, Patrick Deelen ORCID, Androniki Menelaou, Eskil Kreiner-Møller ORCID, Fernando Rivadeneira, Javier Gutierrez-Achury, Harm-Jan Westra ORCID, David van Enckevort, Lude Franke ORCID and other authors.
This paper is available in a repository.
This paper is available in a repository.

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Abstract

Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with 'true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05–0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r 2 , increased from 0.61 to 0.71. We also saw improved imputation accuracy for other European populations (in the British samples, r 2 improved from 0.58 to 0.65, and in the Italians from 0.43 to 0.47). A combined reference set comprising 1000G and GoNL improved the imputation of rare variants even further. The Italian samples benefitted the most from this combined reference (the mean r 2 increased from 0.47 to 0.50). We conclude that the creation of a large population-specific reference is advantageous for imputing rare variants and that a combined reference panel across multiple populations yields the best imputation results. European Journal of Human Genetics advance online publication, 4 June 2014; doi:10.1038/ejhg.2014.19