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Association mapping with high density marker panels

This outline covers topics such as linkage disequilibrium, recombination, HapMap, tag SNPs, basic association, and practical linkage disequilibrium. It also discusses measuring LD, empirical LD analysis with Haploview, visualizing LD, haplotype blocks, and the use of haplotypes in association studies.

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Association mapping with high density marker panels

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  1. Association mapping with high density marker panels Jeffrey Barrett

  2. Outline • Linkage disequilibrium and recombination • HapMap • ‘Tag’ SNPs • Basic association • Practical

  3. Linkage disequilibrium

  4. Linkage disequilibrium time

  5. Indirect association

  6. Measuring LD locus 1 D = 11 - pq locus 2 D´ = D/DMAX r2 = D2/p(1-p)q(1-q)

  7. Theoretical and empirical LD Reich et al. Nature (2001)

  8. LD analysis with Haploview

  9. Genotypes vs haplotypes Genotypes: AA CT CC GA Haplotypes: ACCG / ATCA ACCA / ATCG ATCG / ACCA ATCA / ACCG 2n possible reconstructions n = number of heterozygous sites

  10. Limited haplotype diversity Daly et al, Nat Genet (2001)

  11. Visualizing empirical LD

  12. Haplotype blocks

  13. Haplotype blocks

  14. Haplotype blocks

  15. Haplotype blocks

  16. D´ and r2

  17. D´ in 100kb

  18. D´ in common SNPs, 100kb

  19. r2 in 100kb

  20. HapMap

  21. HapMap samples 90 Yoruba individuals (30 parent-parent-offspring trios) from Ibadan, Nigeria (YRI) 90 individuals (30 trios) of European descent from Utah (CEU) 45 Han Chinese individuals from Beijing (CHB) 45 Japanese individuals from Tokyo (JPT)

  22. Why multiple populations?

  23. HapMap SNPs PHASE I: 1,000,000 successful SNPs across the genome PHASE II: 5,000,000 additional SNPs attempted ~4,000,000 total polymorphic SNPs genomewide Panel %r2 > 0.8 max r2 YRI 81 0.90 CEU 94 0.97 CHB+JPT 94 0.97

  24. Enabling association studies:dbSNP International HapMap Project. Nature (2005).

  25. Tagging Reference panel: HapMap data Tags: SNPs chosen for genotyping with the aim of capturing as much information as possible Tests: statistical tests for association to disease

  26. Pairwise tagging G/C 3 G/A 2 T/C 4 G/C 5 A/T 1 A/C 6 G G G G A A G T T G G A C C C C C C C C C C C C A A A A T T G G G C C C high r2 high r2 high r2 Tags: SNP 1 SNP 3 SNP 6 3 in total Test for association: SNP 1 SNP 3 SNP 6 Carlson et al. (2004) AJHG 74:106

  27. Testing tags for association Genotype tags in cases and controls Each tag is tested for association How can we better use this information?

  28. Use of haplotypes can improve genotyping efficiency G/C 3 G/A 2 T/C 4 G/C 5 A/T 1 A/C 6 G G G G A A G T T G G A A C C C C C C C C C C C C C C C A A A A T T G G G C C C Tags: SNP 1 SNP 3 2 in total Test for association: SNP 1 captures 1+2 SNP 3 captures 3+5 “AG” haplotype captures SNP 4+6 Tags: SNP 1 SNP 3 SNP 6 3 in total Test for association: SNP 1 SNP 3 SNP 6 de Bakker et al. (2005) Nat Genet 37:1217

  29. Efficiency de Bakker et al. (2005) Nat Genet 37:1217

  30. Transferability among populations CEU CEU CEU Utah residents with European ancestry(CEPH) Whites from Los Angeles, CA Botnia, Finland PIW de Bakker et al.

  31. Genome-wide tagging coverage Barrett and Cardon, Nat Genet (2006).

  32. Population structure Marchini, Nat Genet (2004)

  33. Population structure -  Genomic control- genome-wide inflation of median test statistic

  34. Crohn’s collection center Center 3:  = 1.77 All others:  = 1.09

  35. IBS clustering Compute IBS between all pairs of individuals, as well as 270 HapMap samples Create a distance matrix of (1-IBS) Classical multidimensional scaling generates principal components which capture largest fraction of variation

  36. Crohn’s PCA

  37. Genotype calling

  38. Calling wrinkles: > 3 clusters

  39. Plate effects Transition to SSF site

  40. Association: allelic 2 • Assumes: • multiplicative • HW equilibrium

  41. Haploview practical • www.hapmap.org • Find bounding hotspots for CARD15 (>10 cM/Mb) • Download file for this window

  42. Haploview practical • What fraction of the dataset can be captured with 8 pairwise tags? • How much more information can be gained by using multimarker tagging?

  43. Haploview practical Data in F:\barrett Is our result experiment-wide significant?

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