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CARe: The NHLBI’s Candidate Gene Association Resource
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
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
Primary Affiliations of CARe Investigators
Baylor College of Medicine UC San FranciscoBoston University University of AlabamaBroad/MIT University of Arizona Case Western Reserve University University of ChicagoCedars Sinai Medical Center University of MiamiChildren's Hospital Oakland Research Institute University of MinnesotaChildren's Hospital of Philadelphia University of MississippiColumbia University University of North CarolinaHarvard University University of PennsylvaniaJackson State University University of PittsburghJohns Hopkins University University of South AlabamaLoyola University University of VermontMassachusetts General Hospital University of VirginiaMedical College of Georgia University of Washington, SeattleMetroHealth Medical Center, Cleveland University of WisconsinNHLBI UT SouthwesternNorthwestern UT, HoustonStanford University Wake Forest UniversityUC Davis Yeshiva UniversityUC San Diego
The CARe Website: Project Information
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
Structure of CARe
Sub-committees / Chairs
Steering CommitteeChair : Eric Boerwinkle
CARDIAMyriam Fornage
ARICEric Boerwinkle
CHSRuss Tracy
CSSCDGeorge Papanicolaou
FHSLarry Atwood
MesaJ erry Rotter
J HSJ im Wilson
SHHS/CFSSusan Redline
HeartRon Krauss
LungDeborah Meyers
BloodAbdullah Kutlar
BroadStacey Gabriel
NHLBIRich Fabsitz
PennDan Radar
Steering CommitteeChair : Eric Boerwinkle
CARDIAMyriam Fornage
ARICEric Boerwinkle
CHSRuss Tracy
CSSCDGeorge Papanicolaou
FHSLarry Atwood
MesaJ erry Rotter
J HSJ im Wilson
SHHS/CFSSusan Redline
HeartRon Krauss
LungDeborah Meyers
BloodAbdullah Kutlar
BroadStacey Gabriel
NHLBIRich Fabsitz
PennDan Radar
Phenotypes Genotyping Analysis
Informatics
Bruce PsatySusan Heckbert
Larry Atwood Steve Rich
SNP SelectionMyriam Fornage
Publications
Data Release
J im Wilson
J im Wilson J oe Mychaleckyj
Phenotypes Genotyping Analysis
Informatics
Bruce PsatySusan Heckbert
Larry Atwood Steve Rich
SNP SelectionMyriam Fornage
Publications
Data Release
J im Wilson
J im Wilson J oe Mychaleckyj
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
SHHS
FHS
CSSCD
ARIC
CFS
MESA
CHS
JHS
CARDIA
9000
2300
16,464
1400
6566
5451
3414
3777
9000
2300
16,464
1400
6566
5451
3414
3777
4354
700
1761
2349
1792
Cohort Pilot (Sequenom- 35 SNPs)
Phase Two (Infinium-iSelect 50,000 SNPs)
Phase Three (Affy 6.0)
48,372 48,372 10,956
CARe Samples to be Genotyped
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
CARe Pilot SNPsGene Polymorphism Associated Phenotype(s) Peroxisome-proliferator activated receptor gamma
Pro12Ala Diabetes, Obesity, Hypertension, Dyslipidemia
Apolipoprotein E Cys/Arg112 & Cys/Arg158 Dyslipidemia Lipoprotein Lipase S447X Dyslipidemia, Hypertension Cholesteryl ester transfer protein C-1337T; G-971A; C-629A; Taq1B Dyslipidemia Hepatic Lipase C-480T; C-514T Dyslipidemia Apolipoprotein A5 S19W; Q139X(rare) Dyslipidemia Proprotein convertase subtilisin/kexin type 9 (PCSK9)
R46L; L253F; A443T; E670G Dyslipidemia
ATP-sensitive potassium channel KCNJ11
E23K Diabetes
Transcription factor 7-like 2 rs12255372 and rs7903146 Diabetes Beta 2 Adrenergic Receptor Arg16Gly; Gln27Glu Hypertension, Obesity Glucocorticoid receptor N363S Obesity Insulin induced gene 2 (INSIG2) rs7566605 Obesity C-reactive protein rs3091244 Metabolic syndrome, Hypertension Tumor necrosis factor (TNF) alpha G-308A Obesity, Metabolic syndrome Melanocortin-4 receptor V103I Obesity Angiotensinogen M235T; T174M Hypertension Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PPARGC1A)
Gly482Ser Obesity, Diabetes
HNF1 alpha A98V (rare) Diabetes, Obesity Insulin I/D promoter polymorphism Diabetes Beta 3 adrenergic receptor 3 Trp64Arg Obesity; Metabolic syndrome Factor VII G10976A Obesity Plasminogen activator inhibitor-1 (PAI-1)
-675 4G/5G Metabolic syndrome
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)
K121Q Diabetes, Obesity
Angiotensin II receptor Type 1 A1166C Hypertension ACE T-3892C (proxy for I/D) Hypertension, Diabetes Methylenetetrahydrofolate reductase C677T Hypertension, Diabetes
CARe Pilot Phenotypes
SOURCE: the CARe Portal
CARe Phase Two
• All 50,000 CARe samples• “All” phenotypes eligible• Illumina IBC Chip (version 2)• Genotyping projected to begin Spring 2008
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
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
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
CARe Phase Three
• >10,000African American samples from CFS, ARIC, JHS, MESA and CARDIA
• “All” phenotypes eligible• Affymetrix 6.0• Genotyping in progress
CARe Projected Timeline
Sep
Candidate Gene Genotyping
Nov OctDec Jan
2008
Feb Mar Apr May Jun Jul Aug
DNAs shipped to Broad
Proposed CARe Workflow
CHSARIC CARDIA CFS
JHSCSSCD FHS SHHSMESA
DNA Phenotypes
QC’d Genotypes
BroadStandardized Phenotype Data
Harmonized Phenotypes
Analysis Engine
Working Groups
Initial Results
CARe Portal
Proposed CARe Workflow and 15 “High Priority Phenotype” Working Groups
CHSARIC CARDIA CFS
JHSCSSCD FHS SHHSMESA
DNA Phenotypes
QC’d Genotypes
BroadStandardized Phenotype Data
Harmonized Phenotypes
Analysis Engine
Working Groups
Initial Results
CARe Portal
AgingAnthropometryAtrial FibrillationBlood BiomarkersBP/HTNCoronary Heart DiseaseDiabetesECHO/CHFKidney diseaseLipidsPulmonary FunctionSleepStrokeSubclinical AtherosclerosisPeripheral Arterial Disease
CARe High Level StrategyC
oh
ort
sTrait 1 Trait 2 Trait 3 Trait 4
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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