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C ARe: The NHLBI’s C andidate Gene A ssociation Re source

C ARe: The NHLBI’s C andidate Gene A ssociation Re source. C andidate Gene A ssociation Re source: CARe. 4 year grant: 04/2006- 04/2010 GOAL: Cross-cohort analysis of genetic variation in important cardiovascular, lung, blood, sleep traits Genotyping of ~50,000 DNAs

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C ARe: The NHLBI’s C andidate Gene A ssociation Re source

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  1. CARe: The NHLBI’s Candidate Gene Association Resource

  2. Candidate Gene Association Resource: CARe • 4 year grant: 04/2006- 04/2010 • GOAL: Cross-cohort analysis of genetic variation in important cardiovascular, lung, blood, sleep traits • Genotyping of ~50,000 DNAs • Phenotype collection and distribution • 9 CARe cohorts

  3. CARe Cohorts • ARIC: Atherosclerosis Risk in Communities • CARDIA: Coronary Artery Risk Development in Young Adults • CFS: Cleveland Family Study • CHS: Cardiovascular Health Study • CSSCD: Cooperative Study of Sickle Cell Disease • FHS: Framingham Heart Study • JHS: Jackson Heart Study • MESA: Multi-Ethnic Study of Atherosclerosis • SHHS: Sleep Heart Health Study

  4. Primary Affiliations of CARe Investigators

  5. The CARe Website: Project Information

  6. CARe : A Brief History • Contract from NHLBI to Broad Institute • Four year contract, started 4/06 • Extensive effort in year 1 in: • Seeking IRB approval from cohorts to meet new NIH data release policies • SNP selection / project strategy • Year 2 focus on: • DNA transfer • Pilot phenotypes transfer • Pilot genotyping and phenotype standardization

  7. Structure of CARe Sub-committees / Chairs

  8. Review of CARe Genotyping Plan PILOT (Sequenom): -35 SNPs typed on ~50,000 DNAs from all CARe Cohorts Phase II (Illumina iSelect---IBC Chip) -~49,000 SNPs covering ~2100 genes typed on ~50,000 DNAs from all CARe Cohorts Phase III (Affymetrix Human Chip version 6.0) ~1,000,000 SNPs (plus CNVs) typed on ~11,000 DNAs from African-American participants in ARIC, CARDIA, Cleveland Family, JHS and MESA

  9. Cohort Pilot (Sequenom- 35 SNPs) Phase Two (Infinium-iSelect 50,000 SNPs) Phase Three (Affy 6.0) SHHS FHS 9000 9000 CHS 5451 5451 CSSCD 2300 2300 ARIC 16,464 16,464 4354 CFS 1400 1400 700 MESA 6566 6566 1761 JHS 3414 3414 2349 CARDIA 3777 3777 1792 48,372 48,372 10,956 CARe Samples to be Genotyped

  10. CARe Pilot Study • All 50,000 CARe samples* • Sequenom--35 CARe SNPs • Previously-associated “functional” SNPs • 38 SNPs Selected by CARe SNP Subcommittee • Genotyping in progress • 25 pilot phenotypes selected • Phenotypes anticipated to be “consistent” among cohorts • Only baseline values requested • Selected by CARe Phenotypes Subcommittee • Phenotype data received from all but one cohort *NOTE: All DNA will be received during this phase

  11. CARe Pilot SNPs

  12. CARe Pilot Phenotypes SOURCE: the CARe Portal

  13. CARe Phase Two • All 50,000 CARe samples • “All” phenotypes eligible • Illumina IBC Chip (version 2) • Genotyping projected to begin Spring 2008

  14. Design of IBC SNP Panel • Partnership between Penn ITMAT / Broad/ CARe • Goal : develop comprehensive candidate gene SNP panel • Definitively rule-in or role-out associations between cardiovascular phenotypes with genetic variation in specific genes/pathways. • Requirements: - Very large sample sizes with ‘harmonizable’ phenotypes - Improved resolution of genetic variation in specific loci of major interest (preferably < MAF 5%) • Combined effort : 210,000 samples to be scanned

  15. Gene Selection for IBC Panel Genes/loci chosen using four methodologies • 1/ Whole Genome SNP Array (WGA) studies • 2/ Pathway based approaches • 3/ Extensive Literature Review • 4/ Input from a range of vascular disease PIs

  16. SNP Selection Strategy for IBC Panel • Priority 1 ~450 genes • Cosmopolitan tagging of HapMap (MAF>2%, r2 0.8) + SeattleSNPs • ‘forcing in’ specific SNPs of interest e.g. nsSNPs, fSNPs • >13.5K SNPs over 24Mbs versus • 3722 (Affy 500K) 6862 (Affy 6.0) • 4368 (Illumina 550K) 5048 (Illumina 650K) Priority 2 1400 genes • Cosmopolitan tagging of HapMap (MAF>5%, r2 0.55) + SeattleSNPs • >25K SNPs over 75Mbs versus • 11069 (Affy 500K) 20896 (Affy 6.0) • 13299 (Illumina 550K) 15479 (Illumina 650K) Priority 3 250 genes • Selection limited to nsSNPs and known & putatively functional variants

  17. CARe Phase Three • >10,000African American samples from CFS, ARIC, JHS, MESA and CARDIA • “All” phenotypes eligible • Affymetrix 6.0 • Genotyping in progress

  18. CARe Projected Timeline DNAs shipped to Broad Nov Dec Jan 2008 Feb Mar Apr May Jun Jul Aug Sep Oct Candidate Gene Genotyping

  19. CHS CSSCD FHS ARIC CARDIA CFS JHS MESA SHHS Proposed CARe Workflow DNA Phenotypes Standardized Phenotype Data Broad Working Groups QC’d Genotypes Harmonized Phenotypes Analysis Engine Initial Results CARe Portal

  20. CHS CSSCD FHS ARIC CARDIA CFS JHS MESA SHHS Proposed CARe Workflow and 15 “High Priority Phenotype” Working Groups Aging Anthropometry Atrial Fibrillation Blood Biomarkers BP/HTN Coronary Heart Disease Diabetes ECHO/CHF Kidney disease Lipids Pulmonary Function Sleep Stroke Subclinical Atherosclerosis Peripheral Arterial Disease DNA Phenotypes Standardized Phenotype Data Broad Working Groups QC’d Genotypes Harmonized Phenotypes Analysis Engine Initial Results CARe Portal

  21. Trait 1 Trait 2 Trait 3 Trait 4 Cohorts CARe High Level Strategy

  22. The CARe Portal: Data Request and Distribution • Hosted @ Broad Institute • Provides a secure, externally available site for application creation, submission, and dataset access • Users download approved dataset for analyses on their own hardware environment

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