Genomics Resources in WHI. WHI ( ) Extension Study Steering Committee Meeting Seattle, WA May 05-06, 2011

Transcription

1 Genomics Resources in WHI WHI ( ) Extension Study Steering Committee Meeting Seattle, WA May 05-06, 2011

2 WHI Genomic Resources in dbgap Outcomes and traits in AA and Hispanics GWAS-SHARe Sequencing-ESP CVD outcomes and traits GWAS AA and Hispanic-SHARe EA-GARNET, WHIMS Stroke consortium Sequencing-ESP GWAS-identified candidates-page Cancer outcomes (and traits) Same as CVD GWAS-colorectal cancer, NHL and Pancreatic Cancer Candidate Genes PAGE

3 SNP Health Association Resource (SHARe) Population-based genomics resource that facilitates discovery and replication of putative genetic variants association with a wide range of outcomes and quantitative traits GWAS-Affymetrix 6.0 Genotyping completed-in dbgap Annual May update of phenotype data WHI SHARe Population AA (n=8515) Hispanic (n=3642) Link GWAS data to cardiometabolic biomarkers Glucose, insulin Lipids CRP Creatinine Available in November 2011; updated to dbgap in May 2012

4 GWAS of Hormone Treatment and CVD and Metabolic Outcomes (GARNET) Pharmacogenomic study comprehensively exploring SNPs (using GWAS) to identify the genetic variants and mechanisms that influence cardiovascular risk in response to HT GWAS-Illumina Omni Quad 1.0M Total n=5046 (EA 4416; AA 276; Hispanic 158; Other 210) Genotyping completed-qc in progress-in dbgap in Aug 2011 Outcomes Incident CHD (n=520) Stroke (n=350) VTE (n=310) Self-report treated DM (n=1080) Multiple outcomes (n=170) 1:1 matched controls free of all case conditions Link GWAS data to relevant intermediate outcomes Blood pressure, glucose, lipids, coronary artery calcium, sex steroid concentrations, and biomarkers of vascular inflammation and thrombosis Available in April 2012

5 WHIMS+ EA GWAS EA genomics resource that facilitates discovery and replication of putative genetic variants association with a wide range of outcomes and quantitative traits Creates HT cohort with GWAS Allows for more in depth exploration of cognitive traits GWAS-Illumina Omni Express Estimated completion of genotyping-march 2012 In dbgap in May 2012 Exploring genotyping ApoE SNPs separately WHIMS+ Cohort WHIMS EA not in GARNET (n=4660) Selected HT EA in neither GARNET or WHIMS Older >64 (n=280) Younger (n=900) Therefore total HT Cohort with GWAS ( SHARe ppt in HT trials) Link GWAS data to Cardiometabolic biomarkers Complete in late April 2012-available several months later

6 WHI Sequencing Project (WHISP) Identification of possible rare causal variants having large effects on CVD and blood disease-susceptibility Exomic sequencing In the extreme tails of CVD quantitative traits (BMI, hypertension) Well phenotyped unique outcomes (e.g. MI < 55; a fib) Deeply phenotyped referent group for additional cardiovascular, lung and blood traits Data available on dbgap beginning May 2011 WHI participants exome sequenced (total WHI n=2230) BMI/T2DM (n=620) EOMI (n-161) (with 209 EOMI controls) Stroke (n=433) Blood pressure (n-358) Deeply phenotyped referent group (n=450) Replication (n=16,500) Exome chip

7 Population Architecture using Genomics and Epidemiology (PAGE) Goal: Explore putative causal variants of complex diseases identified in GWAS gene-environment interaction risk in disease subtypes and ethnic groups impact on intermediate phenotypes Year 01 SNP selection-31,000 WHI genotyped* CVD: Incident CHD (19 SNPs) n=4250: Stroke (9 SNPs) n=3450 T2D: (21 SNPs) n=4000 Obesity (BMI >40) (12 SNPs) n=1000 Lipids (31SNPs) n=1860 Year 02 SNP selection n=20,420 Cancer: Breast Cancer n=1867;lung Cancer n=1688; Endometrial Cancer n=1014; Ovarian n=667; Melanoma n=1020; NHL n=776; Colorectal cancer n=1319 ECG traits Hormone traits(estrogens, IGF) Metabochip AA n=9400 (genotyped in Year 01) and 3590 in Year Hispanics n=5460 Asians n-3500

8 Opportunities from Genomics Studies Discovery of common (and rare) genetic variants associated with a wide range of quantitative traits and outcomes Meta-analyses Replication Gene-gene and gene-environment studies Exploration of candidate genes Systems biology Method development Deep phenotyping Pharmacogenomics

9 Highlighting the WHI Resource Leveraging the ESP-Imputation of Exomes to SHARe-Chris Carlson Leveraging PAGE-Opportunities to use Metabochip genotyping-riki Peters Type II diabetes-simin Liu