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Genotype imputation background

Using 1,000 Genomes data for imputation in genome-wide association studies 1,000 Genomes Data Tutorial ICHG 2011, Montreal Bryan Howie University of Chicago. 0. 0. 1. 1. 1. 0. 0. 1. 1. 0. 0. 0. 1. 1. 1. 0. 0. 0. 0. 0. 1. 1. 1. 0. 1. 1. 1. 0. 0. 1. 1. 1. 1. 1. 1.

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Genotype imputation background

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  1. Using 1,000 Genomes data for imputation in genome-wide association studies1,000 Genomes Data TutorialICHG 2011, MontrealBryan HowieUniversity of Chicago

  2. 0 0 1 1 1 0 0 1 1 0 0 0 1 1 1 0 0 0 0 0 1 1 1 0 1 1 1 0 0 1 1 1 1 1 1 0 0 0 1 0 0 0 0 0 0 1 0 1 1 0 0 0 1 1 1 1 1 0 0 1 Genotype imputation background Reference haplotypes 1 2 0 0 1 1 1 1 0 ? 0 0 0 1 1 1 0 1 Phenotyped GWAS samples 1 2 0 0 1 1 ? 2 0 0 0 0 1 1 1 1 0 ? 0 2 0 0 1 1 1 1 1 1 1 2 SNPs genotyped on an array

  3. 0 0 1 1 1 0 0 1 1 0 0 0 1 1 1 0 0 0 0 0 1 1 1 0 1 1 1 0 0 1 1 1 1 1 1 0 0 0 1 0 0 0 0 0 0 1 0 1 1 0 0 0 1 1 1 1 1 0 0 1 Genotype imputation background Reference haplotypes 1 ? ? ? 2 ? 0 ? ? ? ? 0 1 ? 1 1 ? ? ? 1 ? 0 ? ? ? ? ? 0 ? 0 0 ? ? ? 1 ? 1 ? ? ? ? 1 0 ? 1 Phenotyped GWAS samples 1 ? ? ? 2 ? 0 ? ? ? ? 0 1 ? 1 ? ? ? ? 2 ? 0 ? ? ? ? 0 0 ? 0 1 ? ? ? 1 ? 1 ? ? ? ? 1 0 ? ? 0 ? ? ? 2 ? 0 ? ? ? ? 0 1 ? 1 1 ? ? ? 1 ? 1 ? ? ? ? 1 1 ? 2 UntypedSNPs

  4. 0 0 1 1 1 0 0 1 1 0 0 0 1 1 1 0 0 0 0 0 1 1 1 0 1 1 1 0 0 1 1 1 1 1 1 0 0 0 1 0 0 0 0 0 0 1 0 1 1 0 0 0 1 1 1 1 1 0 0 1 Association signal Genotype imputation background Reference haplotypes 1 1 2 2 2 0 0 1 2 0 0 0 1 1 1 1 1 1 1 1 0 0 1 2 1 0 0 0 0 0 0 0 1 1 1 1 1 2 1 0 1 1 0 0 1 Phenotyped GWAS samples 1 2 2 2 2 0 0 1 2 0 0 0 1 1 1 2 1 2 2 2 0 0 0 2 2 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 0 0 1 0 0 2 2 2 0 0 2 2 2 2 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2

  5. A brief history of imputationreference panels: HapMap 2, HapMap 3, and the 1,000 Genomes Project

  6. HapMap 2 (2007) CEU Reference panels CHB JPT YRI 1 2 0 0 1 1 GWAS genotypes 1 1 0 0 0 0 0 1 1 1 0 1 1 2 0 0 1 1

  7. HapMap 2 (2007) log10 # of genotypes 11 CEU Reference panels CHB 10 JPT YRI 9 HM2 1 2 0 0 1 1 GWAS genotypes 1 1 0 0 0 0 0 1 1 1 0 1 1 2 0 0 1 1

  8. HapMap 3 (2009) log10 # of genotypes 11 ASW CEU CHD Reference panels CHB MKK 10 LWK JPT TSI GIH YRI MEX 9 HM2 HM3 1 2 0 0 1 1 GWAS genotypes 1 1 0 0 0 0 0 1 1 1 0 1 1 2 0 0 1 1

  9. 1,000 Genomes (2010+) log10 # of genotypes 11 Reference panels 10 9 HM2 HM3 1kG 1 2 0 0 1 1 GWAS genotypes 1 1 0 0 0 0 0 1 1 1 0 1 1 2 0 0 1 1

  10. 1,000 Genomes haplotypes are highly accurate ALL SNPs LOW-FREQUENCY SNPs European ancestry African ancestry Admixed (Americas)

  11. Imputation accuracy depends on your GWAS chip ALL SNPs LOW-FREQUENCY SNPs Omni 2.5M Illumina 550k Affymetrix 500k

  12. Imputation from 1,000 Genomes haplotypes can strengthen association signals. GWAS of Osteoarthritis Day-Williams et al. (AJHG 2011)

  13. Standard Imputation GWAS genotypes 1000G Pilot haplotypes Imputed GWAS genotypes 40 minutes per genome

  14. Standard Imputation GWAS genotypes GWAS genotypes 1000G Pilot haplotypes 1000G Phase I haplotypes Imputed GWAS genotypes Imputed GWAS genotypes 40 minutes per genome 7800 minutes per genome

  15. Standard Imputation Pre-phasing Imputation GWAS genotypes GWAS haplotypes GWAS genotypes GWAS genotypes 25 minutes per genome 1000G Pilot haplotypes 1000G Phase I haplotypes Imputed GWAS genotypes Imputed GWAS genotypes 40 minutes per genome 7800 minutes per genome

  16. Standard Imputation Pre-phasing Imputation GWAS genotypes GWAS genotypes GWAS genotypes GWAS haplotypes 25 minutes per genome 1000G Pilot haplotypes 1000G Phase I haplotypes 1000G Pilot haplotypes Imputed GWAS genotypes Imputed GWAS genotypes Imputed GWAS genotypes 40 minutes per genome 7800 minutes per genome 1 minute per genome

  17. Standard Imputation Pre-phasing Imputation GWAS genotypes GWAS genotypes GWAS genotypes GWAS haplotypes GWAShaplotypes 25 minutes per genome 1000G Pilot haplotypes 1000G Phase I haplotypes 1000G Pilot haplotypes 1000G Phase I haplotypes Imputed GWAS genotypes Imputed GWAS genotypes Imputed GWAS genotypes Imputed GWAS genotypes 40 minutes per genome 7800 minutes per genome 1 minute per genome 24 minutes per genome

  18. Standard Imputation Pre-phasing Imputation GWAS genotypes GWAS genotypes GWAS genotypes GWAS haplotypes GWAShaplotypes 25 minutes per genome 1000G Pilot haplotypes 1000G Phase I haplotypes 1000G Pilot haplotypes 1000G Phase I haplotypes Imputed GWAS genotypes Imputed GWAS genotypes Imputed GWAS genotypes Imputed GWAS genotypes 40 minutes per genome 7800 minutes per genome 1 minute per genome 24 minutes per genome

  19. Getting the latest 1,000 Genomes haplotypes • Phase 1 haplotypes now include SNPs, INDELs, and SVs! • 1,000 Genomes haplotypes are available in the formats required by various imputation programs. For example: • Beagle: http://faculty.washington.edu/browning/beagle/beagle.html • IMPUTE2: http://mathgen.stats.ox.ac.uk/impute/impute_v2.html • MaCH/minimac: http://www.sph.umich.edu/csg/abecasis/MACH/download/ • Thanks for coming!

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