Colon CFR Whole Genome
Association Study
Joint Breast-Colon CFR Steering Committee
Meeting
Bethesda Dec 2005
Graham Casey, Dave Duggan (TGen), Ellen
Goode,Duncan Thomas, John Potter, John Hopper,
Robert Haile on behalf of the Colon CFR
Colon CFR WGA Study Design
• Two Stage design:
Stage I: genome-wide scan of 500,000+ SNPs in
population-based CRC cases and
unrelated controls
Stage II: genotype only “significant” SNPs
from stage I in CRC cases and familial
controls
Satagopan et al. Biometrics. 2002;58(1):163-170. Satagopan and Elston. Epidemiol.
2003;25(2):149-157. Satagopan et al. Biometrics. Sep 2004;60(3):589-597 .
Colon CFR WGA Study Design
• Stage I Study Population:
Drawn from population-based centers
Available DNA and Epidemiology Questionnaire
Non-hispanic whites
Reduce clinical and genetic heterogeneity
(known MSS or MSI-L cases only- exclude
MMR mutation carriers and MSI-H cases)
Genetically enriched (FH, <50)
Satagopan et al. Biometrics. 2002;58(1):163-170. Satagopan and Elston. Epidemiol.
2003;25(2):149-157. Satagopan et al. Biometrics. Sep 2004;60(3):589-597 .
Population-based case-control
952 CRC probands and 1020 controls
FH+ and <50 yr over represented
Genotyping:
500K Affymetrix SNP Chip
Statistical analysis:
SNP- and Haplotype-based
Hierarchical modeling incorporating
prior genomic data
Aim 1
Study Population
Methods
• Population-based case-control study:
Disadvantage : possible population stratification
Advantage: greater power to detect differences
Satagopan et al. Biometrics. 2002;58(1):163-170. Satagopan and Elston. Epidemiol.
2003;25(2):149-157. Satagopan et al. Biometrics. Sep 2004;60(3):589-597 .
Affymetrix 500K GeneChip
•
It is estimated that LD in the north European
population of the USA typically extends 60kb from
common alleles. The 500K chip has marker
spacing every 5.8kb 30% average heterozygosity
and 21% average minor allele frequency
•
Approx 80% genome coverage in caucasians
(r2>0.8: 90%,r2>0.5) when using a multi marker
approach
Genome-Wide Genotyping Te