Download Abdominal Aortic Aneurysm

GREG JONES
SURGERY DEPARTMENT, OTAGO MEDICAL SCHOOL
NEW ZEALAND
1) Perform whole genome analysis for AAA
susceptibility.
2) Validation in separate AAA cohorts.
3) Establish a high-density whole genome elderly
chronic disease free reference data set.
4) Determine specificity of AAA association by
comparison with other vascular disease
phenotypes.

GWAS (Affymetrix SNP 6 Gene Chips)


625 cases versus 625 (AAA free) controls
Validation in 4 separate cohort

New Zealand, United Kingdom, Australia, Iceland

>3,000 cases, 2,000-30,000 controls*
1.
2.
3.
4.
5.
6.
Case phenotype selection criteria
Control selection
Covariate analysis
Validation in independent cohorts
Complete replication of WGA studies
WGA statistical power
Phenotype severity (AAA size)
Pathogenic Heterogeneity
Age and Gender Matched
Screened for AAA (aorta <25mm)
Ethnicity
Concurrent Vascular Disease
Cases and Matching Controls
Second NZ cohort, Western Australia,
Chichester and Leicester United Kingdom,
Iceland/Netherlands
Number of Markers to validate
Expect <25% of GWAS SNPs to validate
NZ AAA GWAS
(625 cases + 625 controls)
Decode Genetics AAA
(1400 cases + 30k ‘controls’)
WTCCC AAA
(2000 cases + 3000 ‘controls’)
Genotyping Platform
Patterns of inheritance / expect effect sizes
Staged design (Hirschhorn& Daly 2005)
Stage 1. GWAS, liberal p-value for putative markers
Stage 2. Re-test in independent secondary cohort,
preferably another GWAS
Stage 3. Validate small set of top hits other cohort
1.
2.
3.
4.
5.
6.
7.
DNA quality!!!
Working within QC guidelines
Affymetrix PCR work flow (48-96 samples)
Budget for 15-20% extra consumables
Genotyping console worklow(batch genotype call)
Data management –BCSNPmax
Plink &Haploview
Andre van Rij
Vicky Phillips
Grace Yu
Otago Vascular Diagnostics
Tony Merriman
Les McNoe
The NZ Vascular Society
Aneurysm Consortium
David Lewis (CDHB)
ThodurVasudevan (WDHB)
Ross Blair (WDHB)
Andrew Hill (ADHB)
Western Australian HIMS / AAA study
Paul Norman (UWA)
BHF Cardiovascular Genetics Lab (UCL)
Steve Humphries
Andy Thompson
Jackie Cooper
The Aneurysm Consortium
Matt Bown (St Georges)
HanyHefez (Chichester)
Wellcome Trust Sanger Institute
This work was supported by the
Health Research Council of New Zealand
DeCodeGenetics