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Office hoursWednesday 3-4pm304A Stanley Hall
Fig. 11.26
Association mapping (qualitative)
Association scan, qualitative
43347G’s797141C’s
controlsosteoarthritisχ2 test
Association scan, quantitative
Association vs. linkage Association vs. linkage
Unrelatedindividuals (usually)
Relatedindividuals
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Association vs. linkage
Unrelatedindividuals (usually)
Relatedindividuals
Extreme of linkage study is one large family; lesslikely that phenotype has multiple genetic causes
(locus heterogeneity).
Association vs. linkage
Strong, easy to detect
Unrelatedindividuals
Relatedindividuals
Association vs. linkage
Strong, easy to detect,but rare in population
Unrelatedindividuals
Relatedindividuals
Association vs. linkage
Strong, easy to detect,but rare in population
Unrelatedindividuals
Relatedindividuals
(e.g. BRCA1)
Association vs. linkage
Strong, easy to detect,but rare in population;may not be reflective ofcommon disease.
Unrelatedindividuals
Relatedindividuals
Association vs. linkage
Strong, easy to detect,but rare in population;may not be reflective ofcommon disease.Also, hard to collect familydata.
Unrelatedindividuals
Relatedindividuals
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Association vs. linkage
Strong, easy to detect,but rare in population;may not be reflective ofcommon disease.Also, hard to collect familydata.
Common but weakeffects
Unrelatedindividuals
Relatedindividuals
Association vs. linkage
Strong, easy to detect,but rare in population;may not be reflective ofcommon disease.Also, hard to collect familydata.
Common but weakeffects; need 1000’sof samples to detect
Unrelatedindividuals
Relatedindividuals
Association vs. linkage
Strong, easy to detect,but rare in population;may not be reflective ofcommon disease.Also, hard to collect familydata.
Common but weakeffects; need 1000’sof samples to detect.If no common cause,can fail.
Unrelatedindividuals
Relatedindividuals
Another key feature ofassociation mapping:
resolution
Association vs. linkage
manyrecombinationshave happenedsince commonancestor;shared regionis small; no co-inheritancebetweendistant markers
Association vs. linkagesmallnumber ofgenerations;individualsshare bigchunks ofgenome;can get co-inheritancebetweendistantmarkers
manyrecombinationshave happenedsince commonancestor;shared regionis small; no co-inheritancebetweendistant markers
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Association vs. linkagesmallnumber ofgenerations;individualsshare bigchunks ofgenome;can get co-inheritancebetweendistantmarkers
manyrecombinationshave happenedsince commonancestor;shared regionis small; no co-inheritancebetweendistant markers
So you need very high densityof markers to get signal in anassociation study, but you getvery high spatial resolution.
Association vs. linkagesmallnumber ofgenerations;individualsshare bigchunks ofgenome;can get co-inheritancebetweendistantmarkers
manyrecombinationshave happenedsince commonancestor;shared regionis small; no co-inheritancebetweendistant markers
In the “old days” of sparsemarkers, linkage analysis was
the best strategy.
Causative variant very close
-log(χ
2 p-
valu
e)
rs377472
But there is a pitfall ofassociation tests: “population
structure”
Diabetes in Native Americans
(1971)
Diabetes in Native Americans
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(1971)
Family studiesindicate it is atleast partlygenetic, notenvironmental.
Diabetes in Native Americans Association mapping causal loci
Typed IgG heavy chains with protein assay.Phenotypes can serve as markers too…
Association mapping causal loci
Typed IgG heavy chains with protein assay.Phenotypes can serve as markers too…
(Multiple proteins from chr 14 region: haplotype)
Association mapping causal loci
32841343no Gm27023Gmcontroldiabetes
Association mapping causal loci
32841343no Gm27023Gmcontroldiabetes
Association mapping causal loci
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32841343no Gm27023Gmcontroldiabetes
Association mapping causal loci
“Gm is protective against diabetes?”
Association mapping causal loci
Self-identified heritage Self-identified heritageMost “full heritage”members don’t havethe haplotype
Self-identified heritageMost “full heritage”members don’t havethe haplotype
The few without N.A.heritage are muchmore likely to havethe haplotype
Gm haplotype is very rare inself-identified 100% Pima
members.
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Gm haplotype is very rare inself-identified 100% Pima
members.
Gm is a marker for Caucasian ancestry.
Association and admixture
Association and admixture Association and admixture
hugealmost negligible
Association and admixture
these are all theCaucasians…
Association and admixtureGm doesn’t look like it hasmuch additional protective
effect if you stratify byfamilial origin first!
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Association and admixture
Caucasian ancestry isassociated with Gm haplotype.
Association and admixture
Caucasian ancestry isassociated with Gm haplotype.Caucasian ancestry isassociated with lower diabetesrisk.
Association and admixture
Caucasian ancestry isassociated with Gm haplotype.Caucasian ancestry isassociated with lower diabetesrisk.But Gm is not associated withlower diabetes risk!
Association and admixture
Cases
Controls
Controls are enriched for Caucasians
Association and admixture
Cases
Controls
=
=
N.A. and Caucasians aredifferent at many loci
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://w
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Association and admixture
Cases
Controls
=
=
At any one of these loci, Caucasian-like allele will beenriched in control samples.
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Association and admixture
Cases
Controls
=
=
Don’t believe any one locus is causative!
Microarrays and genotyping
DNA microarrays
Fig. 10.21
DNA microarrays
Fig. 10.21
Post-genome era:the sequence andlocation of theoligos are known
DNA microarrays
Fig. 1.13
Genotyping by array
Fig. 11.8
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Genotyping by array
Fig. 11.10
Genotyping by array
Fig. 11.10
oligo (human genome fragment) index
Genotyping by array
Fig. 11.10
oligo (human genome fragment) index
Genotyping by array
Fig. 11.10
oligo (human genome fragment) index
Genotyping by array
Fig. 11.10
oligo (human genome fragment) index
Genotyping by array
Fig. 11.10
middle nucleotide onchip oligo
oligo (human genome fragment) index
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Genotyping by array
Fig. 11.10
middle nucleotide onchip oligo
Sample DNA is labeled, allowed to hybridize
Genotyping by array
Fig. 11.10
readout of sample
middle nucleotide onchip oligo
Genotyping by array
Fig. 11.10
readout of sample
middle nucleotide onchip oligo
Genotyping by array
Fabrication technology allows millions of oligos (eachpresent in millions of copies) on a single slide
Genotyping by single-baseextension
Fig. 11.11
Genotyping by single-baseextension
http://www.illumina.com/downloads/InfiniumIIWorkflow.pdf
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High density of markersnecessary for association
