association mapping using local genealogies

Association MappingThrough local genealogies

Bioinformatics Research Center

http://www.birc.au.dk/

Thomas Mailund

http://www.birc.au.dk

http://www.birc.au.dk

“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 polymorphism

Cases (affected)

Controls (unaffected)

Disease Mapping...



Cases (affected)


Markers are locally correlated

Disease Mapping...



Cases (affected)


Search for indirect signals

Indirect Association



Cases (affected)


“Tag” markers Unobserved marker

Indirect Association



Cases (affected)


IndirectMulti-Marker

Association



Cases (affected)


The Ancestral Recombination Graph

Hudson 1990, Griffith and Marjoram 1996

Local PhylogeniesFor each “point” on the chromosome, the ARGdetermines a (local) tree:

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...

Using “Perfect Phylogenies”Use the four-gamete test to find regions thatcan be explained by a tree with no recurrent mutations

Mailund, Besenbacher & Schierup 2006

Using “Perfect Phylogenies”Build trees for each such region


Using “Perfect Phylogenies”Each marker splits a sub-tree in two


Scoring the Clustering

Red=casesGreen=controls

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

Mutation

We can place “mutations” on the tree edges and partition chromosomes into “mutants” and “wild-types” and test for different distributions of cases and controls

Mutants

Wild-types

Mutation

Use average or maximum to score the tree

Average is kosher Bayesian stats; maximum needs to be corrected for over-fitting.

Mutants

Wild-types

Whole genome breast cancer

A single causal mutationMax BF / min p-value used as point estimate

Localisation Accuracy

Localisation Accuracy

Two causal mutationsMax BF / min p-value used as point estimate

Power to detect association

0.05 0.10 0.15

020

4060

8010

0

power

Susceptibility allelle frequency

Perc

enta

ge

QBlossocStudent's t−test

Blossoc(BLOck aSSOCiation)

Homepage: www.birc.au.dk/~mailund/Blossoc

Command line andgraphical user interface(with limited functionality)

http://www.birc.au.dk/~mailund/Blossoc


Blossoc(BLOck aSSOCiation)

Homepage: www.birc.au.dk/~mailund/Blossoc

Fast enough to analysetens of thousands of individuals in hundred of thousands of markers in a few days on a desktop computer...



Thank you!

More information athttp://www.birc.au.dk/~mailund/association-mapping/

http://www.birc.au.dk/~mailund/association-mapping/

http://www.birc.au.dk/~mailund/association-mapping/

association mapping using local genealogies

Health & Medicine