@article{van Leeuwen2014, 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}, author = {van Leeuwen, Elisabeth M. and van den Berg, Leonard H. and van der Velde, K. Joeri and van Oven, Mannis and Deelen, Patrick and van Schaik, Barbera D. C. and van Ommen, Gertjan B. and Menelaou, Androniki and Em, van Leeuwen and Kanterakis, Alexandros and Neerincx, Pieter B. T. and Pulit, Sara L. and van Dijk, Freerk and Elbers, Clara C. and Francesco Palamara, Pier and Lc, Francioli and Medina-Gomez, Carolina and Pe'er, Itsik and Abdellaoui, Abdel and Jj, Hottenga and Kloosterman, Wigard P. and Vermaat, Martijn and Li, Mingkun and Laros, Jeroen F. J. and Francioli, Laurent C. and Lc, Karssen and Kreiner-Møller, Eskil and Stoneking, Mark and de Knijff, Peter and Kayser, Manfred and van Setten, Jessica and Westra, Harm-Jan and Hottenga, Jouke Jan and Rivadeneira, Fernando and Veldink, Jan H. and den Dunnen, Johan T. and Amin, Najaf and Jan Hottenga, Jouke and Kattenberg, Mathijs and Gutierrez-Achury, Javier and Karssen, Lennart C. and Estrada, Karol and Jouke, Jan and van Duijn, Cornelia M. and Bot, Jan and Nijman, Isaäuc J. and Franke, Lude and Mei, Hailiang and Koval, Vyacheslav and Ye, Kai and van Enckevort, David and Lameijer, Eric-Wubbo and Swertz, Morris A. and Moed, Matthijs H. and Hehir-Kwa, Jayne Y. and Handsaker, Robert E. and Hj, Westra and Sunyaev, Shamil R. and Dijkstra, Martijn and Sohail, Mashaal and Hormozdiari, Fereydoun and Marschall, Tobias and Byelas, Heorhiy and Marschall, Schönhuth and Guryev, Victor and Slagboom, P. Eline and Beekman, Marian B. and de Craen, Anton J. M. and Suchiman, H. Eka D. and Hofman, Albert and Boomsma, Dorret I. and Willemsen, Gonneke and Wolffenbuttel, Bruce H. and Platteel, Mathieu and Pitts, Steven J. and de Bakker, Paul I. W. and Potluri, Shobha and Cm, van Duijn and Cox, David R. and Li, Qibin and Li, Yingrui and Du, Yuanping and Consortium, Genome of Netherlands and Chen, Ruoyan and Cao, Hongzhi and Li, Ning and Pi, de Bakker and Cao, Sujie and Wang, Jun and Bovenberg, Jasper A. and Committee, Steering and Wijmenga, Cisca and Genome, and Consortium, Genome Netherlands and Ma, Swertz and van Enckevort, Esther}, doi = {10.1038/ejhg.2014.19}, month = {jun}, title = {Improved imputation quality of low-frequency and rare variants in European samples using the ‘Genome of The Netherlands'}, url = {https://www.nature.com/articles/ejhg201419.pdf}, year = {2014} }