Download - Office hours Wednesday 3-4pm 304A Stanley Hall. Fig. 11.26 Association mapping (qualitative)
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Office hoursWednesday 3-4pm304A Stanley Hall
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Fig. 11.26
Association mapping (qualitative)
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Association scan, qualitative
osteoarthritis controls
C’s 141 797
G’s 47 433
2 test
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Association scan, quantitative
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Association vs. linkage
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Association vs. linkage
Unrelatedindividuals (usually)
Relatedindividuals
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Association vs. linkage
Unrelatedindividuals (usually)
Relatedindividuals
Extreme of linkage study is one large family; less likely that phenotype has multiple genetic causes
(locus heterogeneity).
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Association vs. linkage
Strong, easy to detect
Unrelatedindividuals
Relatedindividuals
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Association vs. linkage
Strong, easy to detect, but rare in population
Unrelatedindividuals
Relatedindividuals
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Association vs. linkage
Strong, easy to detect, but rare in population
Unrelatedindividuals
Relatedindividuals
(e.g. BRCA1)
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Association vs. linkage
Strong, easy to detect, but rare in population;may not be reflective of common disease.
Unrelatedindividuals
Relatedindividuals
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Association vs. linkage
Strong, easy to detect, but rare in population;may not be reflective of common disease.Also, hard to collect family data.
Unrelatedindividuals
Relatedindividuals
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Association vs. linkage
Strong, easy to detect, but rare in population;may not be reflective of common disease.Also, hard to collect family data.
Common but weak effects
Unrelatedindividuals
Relatedindividuals
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Association vs. linkage
Strong, easy to detect, but rare in population;may not be reflective of common disease.Also, hard to collect family data.
Common but weak effects; need 1000’s of samples to detect
Unrelatedindividuals
Relatedindividuals
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Association vs. linkage
Strong, easy to detect, but rare in population;may not be reflective of common disease.Also, hard to collect family data.
Common but weak effects; need 1000’s of samples to detect.If no common cause, can fail.
Unrelatedindividuals
Relatedindividuals
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Another key feature of association mapping:
resolution
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Association vs. linkage
many recombinations have happened since common ancestor;shared region is small; no co-inheritance between distant markers
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Association vs. linkagesmall number of generations; individuals share big chunks of genome; can get co-inheritance between distant markers
many recombinations have happened since common ancestor;shared region is small; no co-inheritance between distant markers
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Association vs. linkagesmall number of generations; individuals share big chunks of genome; can get co-inheritance between distant markers
many recombinations have happened since common ancestor;shared region is small; no co-inheritance between distant markers
So you need very high density of markers to get signal in an association study, but you get very high spatial resolution.
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Association vs. linkagesmall number of generations; individuals share big chunks of genome; can get co-inheritance between distant markers
many recombinations have happened since common ancestor;shared region is small; no co-inheritance between distant markers
In the “old days” of sparse markers, linkage analysis was
the best strategy.
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Causative variant very close-lo
g(2
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rs377472
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But there is a pitfall of association tests: “population
structure”
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Diabetes in Native Americans
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(1971)
Diabetes in Native Americans
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(1971)
Family studies indicate it is at least partly genetic, not environmental.
Diabetes in Native Americans
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Association mapping causal loci
Typed IgG heavy chains with protein assay.Phenotypes can serve as markers too…
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Association mapping causal loci
Typed IgG heavy chains with protein assay.Phenotypes can serve as markers too…
(Multiple proteins from chr 14 region: haplotype)
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Association mapping causal loci
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diabetes control
Gm 23 270
no Gm 1343 3284
Association mapping causal loci
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diabetes control
Gm 23 270
no Gm 1343 3284
Association mapping causal loci
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diabetes control
Gm 23 270
no Gm 1343 3284
Association mapping causal loci
“Gm is protective against diabetes?”
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Association mapping causal loci
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Self-identified heritage
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Self-identified heritageMost “full heritage” members don’t have the haplotype
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Self-identified heritageMost “full heritage” members don’t have the haplotype
The few without N.A. heritage are much more likely to have the haplotype
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Gm haplotype is very rare in self-identified 100% Pima
members.
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Gm haplotype is very rare in self-identified 100% Pima
members.
Gm is a marker for Caucasian ancestry.
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Association and admixture
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Association and admixture
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Association and admixture
hugealmost negligible
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Association and admixture
these are all the Caucasians…
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Association and admixtureGm doesn’t look like it has much additional protective
effect if you stratify by familial origin first!
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Association and admixture
Caucasian ancestry is associated with Gm haplotype.
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Association and admixture
Caucasian ancestry is associated with Gm haplotype.Caucasian ancestry is associated with lower diabetes risk.
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Association and admixture
Caucasian ancestry is associated with Gm haplotype.Caucasian ancestry is associated with lower diabetes risk.But Gm is not associated with lower diabetes risk!
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Association and admixture
Cases
Controls
Controls are enriched for Caucasians
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Association and admixture
Cases
Controls
=
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N.A. and Caucasians are different at many loci
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Association and admixture
Cases
Controls
=
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At any one of these loci, Caucasian-like allele will be enriched in control samples.
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Association and admixture
Cases
Controls
=
=
Don’t believe any one locus is causative!
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Microarrays and genotyping
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DNA microarrays
Fig. 10.21
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DNA microarrays
Fig. 10.21
Post-genome era: the sequence and location of the oligos are known
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DNA microarrays
Fig. 1.13
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Genotyping by array
Fig. 11.8
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Genotyping by array
Fig. 11.10
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Genotyping by array
Fig. 11.10
oligo (human genome fragment) index
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Genotyping by array
Fig. 11.10
oligo (human genome fragment) index
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Genotyping by array
Fig. 11.10
oligo (human genome fragment) index
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Genotyping by array
Fig. 11.10
oligo (human genome fragment) index
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Genotyping by array
Fig. 11.10
middle nucleotide on chip oligo
oligo (human genome fragment) index
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Genotyping by array
Fig. 11.10
middle nucleotide on chip oligo
Sample DNA is labeled, allowed to hybridize
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Genotyping by array
Fig. 11.10
readout of sample
middle nucleotide on chip oligo
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Genotyping by array
Fig. 11.10
readout of sample
middle nucleotide on chip oligo
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Genotyping by array
Fabrication technology allows millions of oligos (each present in millions of copies) on a single slide
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Genotyping by single-base extension
Fig. 11.11
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Genotyping by single-base extension
http://www.illumina.com/downloads/InfiniumIIWorkflow.pdf
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High density of markers necessary for association
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