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Picking SNPs Application to Association Studies

Picking SNPs Application to Association Studies. Dana Crawford, PhD SeattleSNPs PGA University of Washington March 20, 2006. Outline of Tutorial. Concepts of tagSNPs LD and haplotype definitions Haplotype blocks and definitions Tools to identify tagSNPs. Ex: E2F2.

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Picking SNPs Application to Association Studies

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  1. Picking SNPs Application to Association Studies Dana Crawford, PhD SeattleSNPs PGA University of Washington March 20, 2006

  2. Outline of Tutorial • Concepts of tagSNPs • LD and haplotype definitions • Haplotype blocks and definitions • Tools to identify tagSNPs

  3. Ex: E2F2 Average Gene: • 26.5 kb • 130 SNPs • 44 SNPs ≥5% MAF Why Do We Need tagSNPs? Too Many SNPs to Genotype! • Whole Genome: • 15,000,000 SNPs • 6,000,000 SNPs > 5% MAF

  4. Genotype at one site can predict genotype at another site Proportion of sites are correlated SNPs Are Correlated (aka linkage disequilibrium) “the nonindependence ofalleles at different sites.” Pritchard and Przeworski 2001

  5. Measuring Pair-wise SNP Correlations • SNP correlation described by linkage disequilibrium (LD) • Pair-wise measures of LD: D´ and r2 • D = pAB - pApB; D´ = D/Dmax Recombination • r2 = D2 • f(A1)f(A2)f(B1)f(B2) Power

  6. LD Statistics: Practical Uses • r2 is inversely related to power • 1/r2 • 1,000 cases 1,250 cases • 1,000 controls r2=1.0 1,250 controls r2 = 0.80 • D´ is related to recombination history • D´ = 1 no recombination • D´ < 1 historical recombination

  7. Where to Find Population LD Statistics For your gene or region of interest, search • HapMap www.hapmap.org • Perlegen genome.perlegen.com • Environmental Genome Project egp.gs.washington.edu • SeattleSNPs PGA pga.gs.washington.edu

  8. Where to Find Population LD Statistics For your gene or region of interest, search • HapMap www.hapmap.org • Perlegen genome.perlegen.com • Environmental Genome Project egp.gs.washington.edu • SeattleSNPs PGA pga.gs.washington.edu

  9. Visualizing Pair-wise LD

  10. Visualizing Pair-wise LD

  11. 2500 1500 Visualizing Pair-wise LD USF1

  12. Visualizing Pair-wise LD

  13. SeattleSNPs SeattleSNPs + Perlegen

  14. Visualizing Pair-wise LD: Beyond the Gene

  15. Visualizing Pair-wise LD: Beyond the Gene

  16. SeattleSNPs Visualizing Pair-wise LD: Beyond the Gene

  17. Multi-SNP Correlations (aka Haplotypes) “…a unique combination of genetic markers present in a chromosome.” pg 57 in Hartl & Clark, 1997

  18. Collect pedigrees Somatic cell hybrids Rodent Human C/C, A/G C/T, A/A Hybrid TT GG CC AG T/T, G/G C/C, A/G Allele-specific PCR SNP 1 SNP 2 CT AG C/T A/G C/T, A/G Constructing Haplotypes

  19. Constructing Haplotypes Examples of Haplotype Inference Software: EM Algorithm Haploview http://www.broad.mit.edu/mpg/haploview/index.php Arlequin http://lgb.unige.ch/arlequin/ PHASE v2.1 http://www.stat.washington.edu/stephens/software.html HAPLOTYPER http://www.people.fas.harvard.edu/~junliu/Haplo/docMain.htm

  20. Haplotypes in SeattleSNPs • >250 genes re-sequenced in inflammation response • 2 populations: European- and African-descent • PHASEv2.0 results posted on website • Interactive tool (VH1) to visualize and sort haplotypes http://pga.gs.washington.edu

  21. Haplotypes in SeattleSNPs

  22. Haplotypes in SeattleSNPs

  23. Haplotypes in SeattleSNPs

  24. Haplotypes in SeattleSNPs

  25. Haplotypes in SeattleSNPs

  26. Haplotypes in SeattleSNPs

  27. Haplotypes in SeattleSNPs

  28. Haplotypes in SeattleSNPs

  29. Haplotypes in SeattleSNPs

  30. Haplotypes in SeattleSNPs

  31. Haplotypes in SeattleSNPs

  32. Using LD and Haplotypes to Pick tagSNPs • r2 is inversely related to power • 1/r2 • 1,000 cases 1,250 cases • 1,000 controls r2=1.0 1,250 controls r2 = 0.80 • D´ is related to recombination history • D´ = 1 no recombination • D´ < 1 historical recombination Example: LDSelect in GVS Example: Haplotype “blocks”

  33. Discovery genotype data pair-wise LD pick tagSNPs Using LD and Haplotypes to Pick tagSNPs • r2 is inversely related to power • 1/r2 • 1,000 cases 1,250 cases • 1,000 controls r2=1.0 1,250 controls r2 = 0.80 Example: LDSelect

  34. LDSelect: Using LD to Pick tagSNPs • LDSelect • Uses SNP discovery data (not haplotypes) • Finds all correlated SNPs to minimize the total number • Maintains genetic diversity of locus Carlson et al. AJHG (2004)

  35. TagSNPs Are Population Specific African-Americans CRP European-Americans CRP

  36. SNP Selection Using GVS

  37. SNP Selection Using GVS 22 SNPs (>5% MAF) 7 tagSNPs

  38. SNP Selection: tagSNP Data

  39. Side Note: Categorizing tagSNPs • SNP context • Nonrepetitive > repetitive • Location of SNP • Coding > noncoding • Function • Nonsynonymous > synonymous

  40. Categorizing tagSNPs

  41. Haplotypes Pick tagSNPs Genotype samples Pick tagSNPs Infer haplotypes Test for association Haplotypes in Genetic Association Studies Two main approaches with haplotypes:

  42. Recombination Natural selection Haplotype block definition Population history Population demography Haplotypes in Genetic Association Studies Two main approaches with haplotypes: Haplotypes Pick tagSNPs Genotype samples Pick tagSNPs Infer haplotypes Test for association

  43. Represent most chromosomes Few Haplotypes Strong LD Haplotype “Blocks” Daly et al Nat. Genet. (2001) Daly et al 2001

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