Genetic variation: SNPs ATTGCAATCCGTGG...ATCGAGCCATACG ATTGCACGCCG - - PDF document

▶
genetic variation snps
SMART_READER_LITE
LIVE PREVIEW

Genetic variation: SNPs ATTGCAATCCGTGG...ATCGAGCCATACG ATTGCACGCCG - - PDF document

Jun 25, 2023 19 likes •59 views

SIB course 4-8 Feb 2008 Part 2: Statistical analysis applied to genome Whole Genome Association and proteome analyses Sven Bergmann Department of Medical Genetics University of Lausanne Rue de Bugnon 27 - DGM 328 CH-1005 Lausanne

slide-1
SLIDE 1

1

SIB course 4-8 Feb 2008

Statistical analysis applied to genome and proteome analyses

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

Part 2: Whole Genome Association

Overview

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

ATTGCAATCCGTGG...ATCGAGCCA…TACGATTGCACGCCG… ATTGCAAGCCGTGG...ATCTAGCCA…TACGATTGCAAGCCG… ATTGCAAGCCGTGG...ATCTAGCCA…TACGATTGCAAGCCG… ATTGCAATCCGTGG...ATCGAGCCA…TACGATTGCACGCCG… ATTGCAAGCCGTGG...ATCTAGCCA…TACGATTGCAAGCCG…

Genetic variation: SNPs Phenotypic variation:

0.2 0.4 0.6 0.8 1 1.2

  • 6
  • 4
  • 2

2 4 6

What is association?

chromosome SNPs trait variant Genetic variation yields phenotypic variation

Population with ‘ ’ allele Population with ‘ ’ allele

Distributions of “trait”

slide-2
SLIDE 2

2

Quantifying Significance T-test

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

Regression analysis

X

Y

“response” “feature(s)” “intercept” “coefficients” “residuals”

Whole Genome Association Whole Genome Association

Similar approach, but looking at the entire genome!

That is: 500.000 SNPs!

High significance Low significance

Whole Genome Association

* * * * *

Scan Entire Genome

  • 500,000s SNPs

Identify local regions

  • f interest, examine

genes, SNP density gegulatory regions, etc Replicate the finding

slide-3
SLIDE 3

3

Linkage Disequilibrium

Markers close together on chromosomes are often transmitted together, yielding a non-zero correlation between the alleles.

Marker 1 2 3 n LD D

  • 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

Sept 01 Feb 02 April 04 Oct 04 Oct 2002 – 2007…

Building Haplotype Maps for Gene-finding

Imputing SNPs

GWA: >20 publications in 2006/2007

Massive!

Genotypes

6’189 individuals

Phenotypes

159 measurement 144 questions

500.000 SNPs

CoLaus = Cohort Lausanne

Collaboration with: Peter Vollenweider & Gerard Waeber(CHUV)

Analysis of Genotypes only

Principle Component Analysis reveals SNP-vectors explaining largest variation in the data

slide-4
SLIDE 4

4

Ethic groups cluster according to geographic distances

PC1 PC1 PC2 PC2

WGA with different covariates indicate importance of population stratification

Genomic Control Origin of grandparents Principal Components Both

Challenges

  • Multiple Hypothesis testing:

Is one SNP with p=10

  • 6 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, …)

Prospects: Module analysis

BPS=Systolic Blood Pressure

Modular Approach for Integrative Analysis of CoLaus Data

Individuals

Questionaire Or SNPs Measurements

Tests Questions

Module links

Personalized Medicine

… a dream or the future?