Association mapping (qualitative) Association scan, quantitative. Office hours Wednesday 3-4pm 304A Stanley Hall. Association scan, qualitative

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1 Association mapping (qualitative) Office hours Wednesday 3-4pm 304A Stanley Hall Fig Association scan, qualitative Association scan, quantitative osteoarthritis controls χ 2 test C s G s (usually) 1

2 (usually) Strong, easy to detect Extreme of linkage study is one large family; less likely that phenotype has multiple genetic causes (locus heterogeneity). but rare in population but rare in population (e.g. BRCA1) but rare in population; may not be reflective of common disease. but rare in population; may not be reflective of common disease. Also, hard to collect family data. 2

3 Common but weak effects 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 but rare in population; may not be reflective of common disease. Also, hard to collect family data. Another key feature of association mapping: resolution Common but weak effects; need 1000 s of samples to detect. If no common cause, can fail. but rare in population; may not be reflective of common disease. Also, hard to collect family data. many recombinations have happened since common ancestor; shared region is small; no coinheritance distant markers many recombinations have happened since common ancestor; shared region is small; no coinheritance distant markers small number of generations; share big chunks of genome; can get coinheritance distant markers 3

4 small number of generations; share big chunks of genome; can get coinheritance distant markers many recombinations have happened since common ancestor; shared region is small; no coinheritance distant markers So you need very high density of markers to get signal in an association study, but you get very high spatial resolution. small number of generations; share big chunks of genome; can get coinheritance distant markers many recombinations have happened since common ancestor; shared region is small; no coinheritance distant markers In the old days of sparse markers, linkage analysis was the best strategy. -log(χ 2 p-value) Causative variant very close But there is a pitfall of association tests: population structure rs Diabetes in Native Americans Diabetes in Native Americans (1971) 4

5 Diabetes in Native Americans Association mapping causal loci Family studies indicate it is at least partly genetic, not environmental. Typed IgG heavy chains with protein assay. Phenotypes can serve as markers too (1971) Association mapping causal loci 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 Association mapping causal loci diabetes control diabetes control Gm no Gm Gm no Gm

6 Association mapping causal loci Association mapping causal loci Gm is protective against diabetes? Gm no Gm diabetes control Self-identified heritage Self-identified heritage Most full heritage members don t have the haplotype Self-identified heritage Most full heritage members don t have the haplotype Gm haplotype is very rare in self-identified 100% Pima members. The few without N.A. heritage are much more likely to have the haplotype 6

7 Gm haplotype is very rare in self-identified 100% Pima members. Gm is a marker for Caucasian ancestry. almost negligible huge Gm doesn t look like it has much additional protective effect if you stratify by familial origin first! these are all the Caucasians 7

8 Caucasian ancestry is associated with Gm haplotype. Caucasian ancestry is associated with Gm haplotype. Caucasian ancestry is associated with lower diabetes risk. Caucasian ancestry is associated with Gm haplotype. Caucasian ancestry is associated with lower diabetes risk. But Gm is not associated with lower diabetes risk! Cases Controls Controls are enriched for Caucasians Cases Controls = = Cases Controls = = N.A. and Caucasians are different at many loci At any one of these loci, Caucasian-like allele will be enriched in control samples. 8

9 Cases = Microarrays and genotyping Controls = Don t believe any one locus is causative! DNA microarrays DNA microarrays Post-genome era: the sequence and location of the oligos are known Fig Fig DNA microarrays Fig Fig

10 oligo (human genome fragment) index oligo (human genome fragment) index oligo (human genome fragment) index oligo (human genome fragment) index oligo (human genome fragment) index middle nucleotide on chip oligo 10

11 Sample DNA is labeled, allowed to hybridize middle nucleotide on chip oligo middle nucleotide on chip oligo readout of sample middle nucleotide on chip oligo Fabrication technology allows millions of oligos (each present in millions of copies) on a single slide readout of sample Genotyping by single-base extension Genotyping by single-base extension Fig

12 High density of markers necessary for association 12