ku 05 08 2009

Open problems in association mapping

Thomas Mailund

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Bioinformatics Research Centre

Open problems in association mapping

Thomas Mailund

!"!!"#$%&$'()*"%(+,&&&&&&&&&&&&&&&&&&&&&&&

&

Bioinformatics Research Centre

Stuff about

Overview

• Tutorial

• Multi-marker methods - rare(er) variants

• Multi-loci methods - epistasis

Tutorial

“Genetic” diseases

Gunshot w

oundsC

ar accidents

Smoking induced

lung cancer

Cardiovascular

diseaseO

besityD

iabetes 2

Alzheim

erSchizophrenia

BRC

A1

breast cancer

Cystic fibrosis

Haem

ophilia

Disease mapping...

--A--------C--------A----G---X----T---C---A------T--------G--------A----G---X----C---C---A------A--------G--------G----G---X----C---C---A------A--------C--------A----G---X----T---C---A------T--------C--------A----G---X----T---C---A------T--------C--------A----T---X----T---A---A----

--A--------C--------A----G---X----T---C---A------A--------C--------A----G---X----T---C---A------A--------C--------A----G---X----T---C---G------T--------C--------A----T---X----T---C---A------A--------C--------A----G---X----T---C---A------A--------C--------G----T---X----C---A---A------A--------C--------A----G---X----C---C---G----

Locate disease-affecting polymorphisms

Cases (affected)

Controls (unaffected)

Disease mapping...



Locate phenotype-affecting polymorphisms

Disease mapping...



Cases (affected)


Markers are locally correlated

Marker RelatednessLinkage disequilibrium (LD)

Recombination rate

LD (

r2 )

Empirical Results Theoretical Results

Clark et al. 2003, AJHG 73:285-300. Hein et al. 2005



Cases (affected)


Search for indirect signals

Disease mapping...

Indirect Association



Cases (affected)


“Tag” markers Unobserved marker




Cases (affected)


GWA

Type 500k - 1m and get 3b

GWA

Type 500k - 1m and get 3bThe common

variants

Multiple test issues

5% significance threshold means 5% false positives...

Null distributionAlternative distribution

Null distribution"Real" null distributionAlternative distribution

WTCCC results

GWA a successful approach

~500 validated findings for ~100 different traits

GWA a successful approach

~500 validated findings for ~100 different traits...but much genetic risk remains unexplained!

Why?

• Rare variants?

• We only tag common variants...

• Gene-gene interaction?

• Marginal effects vs interactions...

Multi-marker methods




Cases (affected)


IndirectMulti-Marker

Association



Cases (affected)


Local trees along the genome

Trees and LD

Recombination rate

Tree

sim

ilari

ty

Recombination rate

LD r

2

Clustering on a tree

Disease affecting mutation


Complete penetrance

Incomplete penetrance

Spurious disease


60%

40%

25%

75%

Case/control clusteringis not random on the tree...

Scoring the clustering

Red=casesGreen=controls

Are the case chromosomes significantly over-represented in some clusters?

Besenbacher et al. 2009

Multi-loci methods

AAAGG

AAAGG

A 3 2

G 3 2

0

1.5

3

A G

T 2 3

A 2 3

0

1.5

3

T A

TTAAA

AAATT

AAAGG

AAAGG

TTAAA

AAATT

AT 2 0

AA 1 1

GA 2 0

GT 0 2

0

1

2

AT AA GA GT

Explosion in complexity

500k markers gives us ~125 billion pairs!

Explosion in complexity

500k markers gives us ~2·1016 triplets

• Using protein interaction networks we

• Reduced ~125 billion tests to ~3-4 million

• Reduced corrected significance threshold from ~4·10-13 to ~9·10-8

Perspectives...

• Complete genome sequencing

• No need for tagging

• Rare variants

• Structural variation

• Pathway analysis

• Analysis of pathways as a whole

• Constructing tests from known pathways

ku 05 08 2009

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