title: Improved imputation quality of low-frequency and rare variants in European samples using the 'Genome of The Netherlands'.
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.
authors.affiliation: 1] University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands [2] University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.
authors.forename: Patrick
authors.identifier: 0000000256543966
authors.initials: P
authors.lastname: Deelen
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Androniki
authors.initials: A
authors.lastname: Menelaou
authors.affiliation: Department of Epidemiology, Genetic Epidemiology Unit, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: 1] University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands [2] University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Kanterakis
authors.affiliation: 1] University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands [2] University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.
authors.forename: Freerk
authors.initials: F
authors.lastname: van Dijk
authors.affiliation: 1] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands [2] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [3] Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands.
authors.forename: Carolina
authors.initials: C
authors.lastname: Medina-Gomez
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Laurent C
authors.initials: LC
authors.lastname: Francioli
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jouke Jan
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Department of Epidemiology, Genetic Epidemiology Unit, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Lennart C
authors.initials: LC
authors.lastname: Karssen
authors.affiliation: 1] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands [2] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [3] Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA [4] Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.affiliation: 1] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands [2] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [3] COPSAC; Copenhagen Prospective Studies on Asthma in Childhood; Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Eskil
authors.identifier: 0000000312042438
authors.initials: E
authors.lastname: Kreiner-Møller
authors.affiliation: 1] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands [2] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [3] Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: van Setten
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Harm-Jan
authors.identifier: 000000017038567X
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: 1] University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands [2] NBIC BioAssist, Netherlands Bioinformatics Center, Nijmegen, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: van Enckevort
authors.affiliation: 1] University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands [2] University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Dijkstra
authors.affiliation: 1] University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands [2] University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.
authors.forename: Heorhiy
authors.initials: H
authors.lastname: Byelas
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: 1] Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands [2] Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands [3] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [4] Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: 1] University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands [2] University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.
authors.forename: Morris A
authors.initials: MA
authors.lastname: Swertz
mesh_terms: D016022:Case-Control Studies; D016000:Cluster Analysis; D003718:Denmark; D005787:Gene Frequency; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D007558:Italy; D009426:Netherlands; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D006113:United Kingdom; D044465:White People / Q000235:genetics*