title: Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel.
abstract: Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Adaptive Biotechnologies Corporation, Seattle Washington 98102, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Howie
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Memari
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Walter
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Clifton, Bristol BS8 2BN, UK.
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Petr
authors.initials: P
authors.lastname: Danecek
authors.affiliation: Biology and Genetics, Department of Life and Reproduction Sciences, University of Verona, 37134, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Malerba
authors.affiliation: Biology and Genetics, Department of Life and Reproduction Sciences, University of Verona, 37134, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Trabetti
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2.|Department of Medicine, McGill University, Montreal, Quebec, Canada H3A 1B1.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1B1.
authors.forename: Hou-Feng
authors.initials: HF
authors.lastname: Zheng
authors.affiliation: Division of Nephrology and Dialysis, Institute of Internal Medicine, Renal Program, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2.|Department of Medicine, McGill University, Montreal, Quebec, Canada H3A 1B1.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1B1.|The Department of Twin Research &Genetic Epidemiology, King's College London, St Thomas' Campus, Lambeth Palace Road, London SE1 7EH, UK.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Richard
authors.identifier: http://orcid.org/0000-0002-9130-1006
authors.initials: R
authors.lastname: Durbin
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Clifton, Bristol BS8 2BN, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.|Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Jonathan
authors.identifier: http://orcid.org/0000-0003-0610-8322
authors.initials: J
authors.lastname: Marchini
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.|Department of Haematology, University of Cambridge, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Nicole
authors.identifier: http://orcid.org/0000-0003-1095-3852
authors.initials: N
authors.lastname: Soranzo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D005787:Gene Frequency; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom; D044465:White People / Q000235:genetics*; D055815:Young Adult