Association mapping with high density marker panels
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Association mapping with high density marker panels. Jeffrey Barrett. Outline. Linkage disequilibrium and recombination HapMap ‘Tag’ SNPs Basic association Practical. Linkage disequilibrium. Linkage disequilibrium. time. Indirect association. Measuring LD. locus 1. D =  11 - pq.

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Outline
Outline

  • Linkage disequilibrium and recombination

  • HapMap

  • ‘Tag’ SNPs

  • Basic association

  • Practical





Measuring ld
Measuring LD

locus 1

D = 11 - pq

locus 2

D´ = D/DMAX

r2 = D2/p(1-p)q(1-q)


Theoretical and empirical ld
Theoretical and empirical LD

Reich et al. Nature (2001)



Genotypes vs haplotypes
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


Limited haplotype diversity
Limited haplotype diversity

Daly et al, Nat Genet (2001)










R 2 in 100kb
r2 in 100kb



Hapmap samples
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)



Hapmap snps
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


Enabling association studies dbsnp
Enabling association studies:dbSNP

International HapMap Project. Nature (2005).


Tagging
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


Pairwise tagging
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


Testing tags for association
Testing tags for association

Genotype tags in cases and controls

Each tag is tested for association

How can we better use this information?


Use of haplotypes can improve genotyping efficiency
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


Efficiency
Efficiency

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


Transferability among populations
Transferability among populations

CEU

CEU

CEU

Utah residents with European ancestry(CEPH)

Whites from

Los Angeles, CA

Botnia, Finland

PIW de Bakker et al.


Genome wide tagging coverage
Genome-wide tagging coverage

Barrett and Cardon, Nat Genet (2006).


Population structure
Population structure

Marchini, Nat Genet (2004)


Population structure1
Population structure -

Genomic control-

genome-wide inflation of median test statistic


Crohn s collection center
Crohn’s collection center

Center 3:  = 1.77

All others:  = 1.09


Ibs clustering
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





Plate effects
Plate effects

Transition to SSF site


Association allelic 2
Association: allelic 2

  • Assumes:

    • multiplicative

    • HW equilibrium


Haploview practical
Haploview practical

  • www.hapmap.org

  • Find bounding hotspots for CARD15 (>10 cM/Mb)

  • Download file for this window


Haploview practical1
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?


Haploview practical2
Haploview practical

Data in F:\barrett

Is our result experiment-wide significant?


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