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Sven Bergmann Part2

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Jingkui Wang
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16 views4 pages

Sven Bergmann Part2

Uploaded by

Jingkui Wang
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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SIB course 4-8 Feb 2008

Statistical analysis applied to genome Part 2:


and proteome analyses Whole Genome Association

Sven Bergmann
Department of Medical Genetics
University of Lausanne
Rue de Bugnon 27 - DGM 328
CH-1005 Lausanne
Switzerland

work: ++41-21-692-5452
cell: ++41-78-663-4980
http://serverdgm.unil.ch/bergmann

Overview Genetic variation: SNPs


ATTGCAATCCGTGG...ATCGAGCCA…TACGATTGCACGCCG…

• Basics
• What is association? ATTGCAAGCCGTGG...ATCTAGCCA…TACGATTGCAAGCCG…

• Whole genome association ATTGCAAGCCGTGG...ATCTAGCCA…TACGATTGCAAGCCG…

• CoLaus Study ATTGCAATCCGTGG...ATCGAGCCA…TACGATTGCACGCCG…

• Challenges
ATTGCAAGCCGTGG...ATCTAGCCA…TACGATTGCAAGCCG…

Phenotypic variation: What is association?


SNPs trait variant chromosome

Genetic variation
1.2
yields phenotypic variation
1

0.8
Population with ‘ ’ allele Population with ‘ ’ allele
0.6

0.4

0.2

0
-6 -4 -2 0 2 4 6
Distributions of “trait”

1
Quantifying Significance T-test

t-value (significance) can be translated into p-value (probability)

Regression analysis Whole Genome Association

“residuals”
“intercept”
“coefficients”

“response”

X “feature(s)”

Whole Genome Association Whole Genome Association


High Scan Entire Genome * *
significance - 500,000s SNPs

* **
Identify local regions
Low of interest, examine
genes, SNP density
significance gegulatory regions, etc

Similar approach,
but looking at the entire genome!
Replicate the finding

That is: 500.000 SNPs!

2
Building Haplotype Maps for Gene-finding
Linkage Disequilibrium
D
1. Human Genome Project
Marker 1 2 3 n
Good for consensus,
not good for individual
LD differences
Sept 01 Feb 02 April 04 Oct 04

2. Assay genetic variants


Verify polymorphisms,
catalogue correlations
Markers close together on chromosomes amongst sites
Anonymous with respect to
Oct 2002 – 2007…
are often transmitted together, yielding a traits

non-zero correlation between the alleles.

Imputing SNPs GWA: >20 publications in 2006/2007

Massive!

CoLaus = Cohort Lausanne Analysis of Genotypes only


individuals
6’189

Phenotypes Genotypes

159 measurement
500.000 SNPs
144 questions

Principle Component Analysis reveals SNP-vectors


Collaboration with: explaining largest variation in the data
Peter Vollenweider & Gerard Waeber(CHUV)

3
Ethic groups cluster according to WGA with different covariates
geographic distances indicate importance of population
stratification
Genomic Control Origin of grandparents
PC2

Principal Components Both


PC2

PC1 PC1

Prospects: Module analysis


Challenges
• Multiple Hypothesis testing: BPS=Systolic Blood Pressure
-6
Is one SNP with p=10 a significant result
when testing 500.000 SNPs?
• Covariates & Interactions
For what do we have to correct the
phenotypes?
(Age, sex, treatments, other SNPs …)
• Data Integration
How to validate finding?
(Replication Studies, Meta-Analyses,
Re-sequencing, Function Studies, …)

Modular Approach for Integrative


Analysis of CoLaus Data Personalized Medicine
Measurements
Tests

Module
Individuals
links

… a dream or
Questions

Questionaire the future?


Or
SNPs

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