Outline

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Outline

• Basics
• What is association?
• Whole genome association
• CoLaus Study
• Challenges

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Genetic variation SNPs
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Phenotypic variation
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What is association?
chromosome
SNPs
trait variant
Genetic variation yields phenotypic variation
Population with allele
Population with allele
Distributions of trait
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Quantifying Significance
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T-test
t-value (significance) can be translated into
p-value (probability)
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Whole Genome Association
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Whole Genome Association
Similar approach, but looking at the entire
genome! That is 500.000 SNPs!
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Whole Genome Association
Scan Entire Genome - 500,000s SNPs
Identify local regions of interest,
examine genes, SNP density gegulatory regions, etc
Replicate the finding
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Linkage Disequilibrium
D
1
2
3
n
Marker
LD
Markers close together on chromosomes are often
transmitted together, yielding a non-zero
correlation between the alleles.
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Building Haplotype Maps for Gene-finding
1. Human Genome Project ? Good for consensus,
not good for individual differences
2. Assay genetic variants ? Verify
polymorphisms, catalogue correlations
amongst sites ? Anonymous with respect to
traits
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Imputing SNPs
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GWA gt20 publications in 2006/2007
Massive!
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CoLaus Cohort Lausanne
Genotypes
Phenotypes
6189 individuals
159 measurement 144 questions
500.000 SNPs
Collaboration withPeter Vollenweider Gerard
Waeber(CHUV)
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Analysis of Genotypes only
Principle Component Analysis reveals SNP-vectors
explaining largest variation in the data
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Ethic groups cluster according to geographic
distances
PC2
PC2
PC1
PC1
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WGA with different covariates indicate importance
of population stratification
Genomic Control
Origin of grandparents
Both
Principal Components
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Challenges

• Multiple Hypothesis testingIs one SNP with
  p10-6 a significant result when testing 500.000
  SNPs?
• Covariates InteractionsFor what do we have to
  correct the phenotypes?(Age, sex, treatments,
  other SNPs )
• Data IntegrationHow to validate
  finding?(Replication Studies, Meta-Analyses,
  Re-sequencing, Function Studies, )

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Prospects Module analysis
BPSSystolic Blood Pressure
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Modular Approach for Integrative Analysis of
CoLaus Data
Measurements
Questions
Questionaire Or SNPs
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Personalized Medicine
a dream or the future?