title: Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel.
abstract: A major use of the 1000 Genomes Project (1000 GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000 GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants.
authors: Department of Statistics, University of Oxford, Oxford OX1 3TG, UK.
authors: Olivier
authors: O
authors: Delaneau
authors: 1] Department of Statistics, University of Oxford, Oxford OX1 3TG, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors: Jonathan
authors: J
authors: Marchini
mesh_terms: D000465:Algorithms; D000483:Alleles; D005787:Gene Frequency; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D046228:Microarray Analysis / Q000706:statistics & numerical data*; D020641:Polymorphism, Single Nucleotide
references: G3 (Bethesda). 2011 Nov;1(6):457-70
references: 22384356
references: Nature. 2012 Nov 1;491(7422):56-65
references: 23128226
references: Bioinformatics. 2011 Nov 1;27(21):2987-93
references: 21903627
references: Nat Methods. 2012 Feb;9(2):179-81
references: 22138821
references: Nat Rev Genet. 2011 Jun;12(6):443-51
references: 21587300
references: Am J Hum Genet. 2009 Feb;84(2):210-23
references: 19200528
references: Nat Rev Genet. 2010 Jul;11(7):499-511
references: 20517342
references: Genome Res. 2013 May;23(5):833-42
references: 23296920
references: Nat Genet. 2011 May;43(5):491-8
references: 21478889
references: Bioinformatics. 2013 Jan 1;29(1):84-91
references: 23093610
references: Genet Epidemiol. 2010 Dec;34(8):816-34
references: 21058334
references: Bioinformatics. 2013 Sep 15;29(18):2245-52
references: 23825370
references: Nat Genet. 2011 Mar;43(3):269-76
references: 21317889
references: Nat Methods. 2013 Jan;10(1):5-6
references: 23269371
references: Am J Hum Genet. 2013 Oct 3;93(4):687-96
references: 24094745
references: Bioinformatics. 2013 Oct 1;29(19):2427-34
references: 23943637
references: PLoS Genet. 2009 Jun;5(6):e1000529
references: 19543373