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CARe: The NHLBI’s Candidate Gene Association Resource.

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Presentation on theme: "CARe: The NHLBI’s Candidate Gene Association Resource."— Presentation transcript:

1 CARe: The NHLBI’s Candidate Gene Association Resource

2 Candidate Gene Association Resource: CARe 4 year grant: 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 SHHS FHS CSSCD ARIC CFS MESA CHS JHS CARDIA , , CohortPilot (Sequenom- 35 SNPs) Phase Two (Infinium-iSelect 50,000 SNPs) Phase Three (Affy 6.0) 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 (Affy 500K) (Affy 6.0) (Illumina 550K) (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 Sep Candidate Gene Genotyping NovOctDecJan 2008 FebMarAprMayJunJulAug DNAs shipped to Broad

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

20 Proposed CARe Workflow and 15 “High Priority Phenotype” Working Groups CHS ARIC CARDIA CFS JHS CSSCD FHS SHHSMESA DNAPhenotypes QC’d Genotypes Broad Standardized Phenotype Data Harmonized Phenotypes Analysis Engine Working Groups Initial Results CARe Portal 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

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

22 The CARe Portal: Data Request and Distribution 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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