Core Resources Working Group Report. Opportunities for Investigator Engagement

Transcription

1 Core Resources Working Group Report Opportunities for Investigator Engagement

2 Goals of Core Resource Working Group Initial purpose was to explore intervention effects in the 4 clinical trials Extend definition of the interventions Vitamin D validation study (CaD), sex steroid changes (DM and HT), and 4DFR analyses Candidate genes or biomarkers to explain intervention effect New data collection from participants Nutritional biomarkers study, CACS, dietary assessment study Proteomic and genome-wide association studies focused on agnostic examination of protein and genetic variants associated with specific outcomes or CT 70 manuscripts published utilizing core data

3 Goals of Core Resource Working Group Current purpose is to expand the core resource of WHI to facilitate new scientific inquiry and enhance collaborations within and external to WHI Enhance ability to analyze WHI data Nutritional Biomarkers Study, Nutrition and Physical Activity Assessment Study 4DFR food groupings Expand the core dataset CMS Medicare Claims data linkage Medication inventory on WHI Extension participants SEER coding of non-primary cancers SHARe GWAS in African American and Hispanic women Externally funded studies that expand the core dataset and address specific hypotheses PAGE, HT GWAS, and WHISP

4 Population Architecture using Genomics and Epidemiology (PAGE) Funded: NHGRI (Kooperberg and Peters co-pis) 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 SNP selection: Year 01- Incident CHD (19 SNPs), stroke (9 SNPs), T2D (21 SNPs), extreme obesity (BMI >40) (12 SNPs), Lipids (31SNPs) 21,000 WHI participants genotyped Cohorts in consortium include WHI, CALiCO (ARIC, CARDIA, CHS, Strong Heart, Hispanic Community Heart study), NHANES Will better define genotypes of WHI population that can be used in study design and analyses Genotyping of up to 72,000 ppt for 50 putative genetic variants

5 GWAS of Hormone Treatment and CVD and Metabolic Outcomes (HT GWAS) Funded: NHGRI (Reiner PI) Pharmacogenomic study comprehensively exploring SNPs using GWAS technology to identify the genetic variants and mechanisms that influence cardiovascular risk in response to HT case-cohort sample including 744 CHD, 600 stroke, 544 VTE, and 1,677 incident diabetes cases and 3,565 matched controls from the WHI-HT replication genotyping of top hits in an independent sample of cases and controls selected from the WHI-OS Link GWAS data to relevant intermediate outcomes Blood pressure, glucose, lipids, coronary artery calcium, sex steroid concentrations, and biomarkers of vascular inflammation and thrombosis Will increase GWAS results available in WHI by 5500 Will not include ppt who underwent GWAS in SHARe

6 WHI Sequencing Project (WHISP) Funded: NHLBI (ARRA GO) (Jackson, Carlson, Peters, North co-pis) 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 Well phenotyped unique outcomes (e.g. MI < 55; a fib) Validation of newly discovered coding variants by selective genotyping in the remaining cohort (or other populations) assess the role of these causal variants in relation to other CVDrelated traits and pathways. Pathway analysis on selected variants to assess whether a particular pathway is enriched with disease risk-associated genes Will provide exomic sequencing in up to 5500 WHI participants Will preferentially choose ppt with additional biomarkers or who have undergone GWAS through SHARe or other WH ancillary studies

7 Exome Definition CCDS, RefSeq, Ensembl split amongst 160, ,000 exons total length of megabases include named genes, canonical splice-sites, mirnas excludes 5 & 3 UTRs (untranslated)

8 Exome Enrichment Options Molecular inversion probes Array hybridization In solution hybridization

9 Solution Hybridization Capture Protocol hyb gdna library prep Shotgun Library biotin probes streptavidin bead cleanup elute wash captured DNA

10 Illumina Sequencing Protocol Input library Cluster generation Sequencing

11 ESP Phenotypes Focused on extremes Phenotypes selected for exomic sequencing BMI-T2DM LDL Early MI (<50 male; <60 female) Blood pressure Stroke Deeply phenotyped referent group

12 Example of Results Psudomonas infection in CF Lung GO: Phase 1 (Average for 60 samples) Concordance (FingerPrint) 99.7% Unique reads to target Mean depth 32.9 M 74x Coverage (>8x) 92% Coverage (>20x) 84% Variants (all) 15,166 % in dbsnp Variants (novel) 947 Ti/Tv (known) 3.24 Ti/Tv (novel) 2.68

13 Example of Overall Summary Statistics 37 from early onset chronic Pa extreme, 26 from never/late extreme Total Number of variants observed: 68,337 Total Number of genes observed: 13,602 Number of Novel variants: 25,085 (36%) Percent of variants that are novel for autosomal chromosomes: range = 28% to 41% (X: 48%, Y: 63%) Nonsynonymous: ~ 50% overall; ~ 35% of novel variants Map by chromosome of variant locations and frequencies: in progress

14 Current Status of Core Resource Biorepository has adequate sample for many but not all outcomes 70-95% of cases have more than 1 ml of plasma and serum available; many have 2.0 ml or greater Core Financial Resources Approximately $2.5M uncommitted Committed $700k for SHARe biomarkers Held aside $700k for MRC biomarkers GWAS data will be available on approximately 22-24,000 participants Affymetrix 6.0 from SHARe Illumina 550 or 610k from PanScan, hip fracture BAA and colorectal ancillary study HT GWAS Biomarker data from ancillary studies Track data by outcome and assay

15 Goals of WHI SHARe Program GWAS of Minority Participants in WHI Allows for association studies of quantitative traits and intermediate outcomes When combined with other cohorts can examine associations with outcomes Can serve as validation of genetic variants identified in other GWAS Can be used to examine pathways (candidate genes) Potential to contribute to gene-gene and geneenvironment analyses Complements GWAS in cohorts already included in SHARe (primarily white)

16 WHI SHARe GWAS Cohort Black and Hispanic women participants in WHI All have signed supplemental consent Details and study ID listed on WHIOPS Genotyping platform Affymetrix 6.0 Phenotype data available WHI study-wide data (includes intermediate variables and traits, exposures and outcomes) Core biomarker data CVD biomarkers, sex steroids, vitamin D in CaD etc DEXA data Ancillary study and BAA data to be included with subsequent data additions

17 WHI SHARe Structure WHI ESEC SHARe Oversight WG SHARe GWAS Publications WG SHARe Scientific WGs SHARe Analysis WG Collaborations Phenotypesw other cohorts Exposures Special Populations

18 SHARe Analytic Approach Centralized data cleanup-ccc and NHLBI Facilitate efficient SHARe analyses within protected publication timeframe Begins Nov 2009 Creation of a centralized analytic resource 4 centers selected FHCRC (Kooperberg) UNC (Heiss) Oakland (Risch) Wake Forest (Snively) Total analytic capacity ~40 ms Work collaboratively to develop an organizational approach to some analytic issues Communication strategies to share approaches

19 SHARe Publications Approach Request for topics Pre-review to determine overlap Template for manuscript proposals developed 36 proposals received in initial request Others can be submitted through regular P&P process Special GWAS P&P review sub-group Prioritize ms for access to centralized analytic resource After approval will be sent out to WHI for additional authorship slots Will be assigned to analysis center based on lead author preference, scientific expertise of analysis center and workload Authorship slots for external content experts and cohort collaborators

20 WHI SHARe Collaborations with other cohorts WHI SHARe Discovery Replication Joint Analyses Other Cohort(s) Replication Discovery Most replication will be in silico Identify potential collaborative cohorts Similar phenotypes Related phenotypes Ethnic-racial minorities Both formal and informal collaborations CARE and Framingham Harmonize phenotypes and exposures Explore ethics issues