1. G REG J ONES S URGERY D EPARTMENT, O TAGO M EDICAL S CHOOL N EW Z EALAND

4. 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.

5.  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*

6. 1. Case phenotype selection criteria 2. Control selection 3. Covariate analysis 4. Validation in independent cohorts 5. Complete replication of WGA studies 6. WGA statistical power

7. Phenotype severity (AAA size) Pathogenic Heterogeneity

8. Age and Gender Matched Screened for AAA (aorta <25mm) Ethnicity Concurrent Vascular Disease

9. 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

10. NZ AAA GWAS (625 cases + 625 controls) (625 cases + 625 controls) Decode Genetics AAA (1400 cases + 30k ‘controls’) WTCCC AAA (2000 cases + 3000 ‘controls’) Genotyping Platform

11. 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

12. 1.DNA quality!!! 2.Working within QC guidelines 3.Affymetrix PCR work flow (48-96 samples) 4.Budget for 15-20% extra consumables 5.Genotyping console worklow (batch genotype call) 6.Data management –BCSNPmax 7.Plink &Haploview

13. 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) 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 DeCodeGenetics This work was supported by the Health Research Council of New Zealand