Transcript Media:CARe_slides_2008

CSSCD
Cleveland
Family
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ARe
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
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CARe Cohorts
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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
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Primary Affiliations of CARe Investigators
Baylor College of Medicine
Boston University
Broad/MIT
Case Western Reserve University
Cedars Sinai Medical Center
Children's Hospital Oakland Research Institute
Children's Hospital of Philadelphia
Columbia University
Harvard University
Jackson State University
Johns Hopkins University
Loyola University
Massachusetts General Hospital
Medical College of Georgia
MetroHealth Medical Center, Cleveland
NHLBI
Northwestern
Stanford University
UC Davis
UC San Diego
UC San Francisco
University of Alabama
University of Arizona
University of Chicago
University of Miami
University of Minnesota
University of Mississippi
University of North Carolina
University of Pennsylvania
University of Pittsburgh
University of South Alabama
University of Vermont
University of Virginia
University of Washington, Seattle
University of Wisconsin
UT Southwestern
UT, Houston
Wake Forest University
Yeshiva University
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The CARe Website: Project Information
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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
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Structure of CARe
Steering Committee
Chair : Eric Boerwinkle
ARIC
Eric Boerwinkle
CARDIA
CHS
Myriam Fornage
CSSCD
FHS
Russ Tracy George Papanicolaou
Mesa
JHS
SHHS/CFS
Heart
Jerry Rotter
Jim Wilson
Susan Redline
Larry Atwood
Lung
Blood
Ron Krauss Deborah Meyers Abdullah Kutlar
Broad
NHLBI
Stacey Gabriel
Rich Fabsitz
Penn
Dan Radar
Sub-committees / Chairs
Phenotypes
Genotyping
Analysis
Data Release
Bruce Psaty
Susan Heckbert
Larry Atwood
Steve Rich
Jim Wilson
SNP Selection
Myriam Fornage
Publications
Informatics
Jim Wilson
Joe Mychaleckyj
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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
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CARe Samples to be Genotyped
Cohort
Pilot
Phase Two
Phase Three
(Sequenom35 SNPs)
(Infinium-iSelect
50,000 SNPs)
(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
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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
CSSCD
*NOTE: All DNA will be received during this phase
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CARe Pilot SNPs
Gene
Peroxisome-proliferator activated
receptor gamma
Apolipoprotein E
Lipoprotein Lipase
Cholesteryl ester transfer protein
Hepatic Lipase
Apolipoprotein A5
Proprotein convertase
subtilisin/kexin type 9 (PCSK9)
ATP-sensitive potassium channel
KCNJ11
Transcription factor 7-like 2
Beta 2 Adrenergic Receptor
Glucocorticoid receptor
Insulin induced gene 2 (INSIG2)
C-reactive protein
Tumor necrosis factor (TNF) alpha
Melanocortin-4 receptor
Angiotensinogen
Peroxisome proliferator-activated
receptor-gamma co-activator-1alpha
(PPARGC1A)
HNF1 alpha
Insulin
Beta 3 adrenergic receptor 3
Factor VII
Plasminogen activator inhibitor-1
(PAI-1)
Ectonucleotide
pyrophosphatase/phosphodiesterase
1 (ENPP1)
Angiotensin II receptor Type 1
ACE
Methylenetetrahydrofolate reductase
Polymorphism
Pro12Ala
Cys/Arg112 & Cys/Arg158
S447X
C-1337T; G-971A; C-629A; Taq1B
C-480T; C-514T
S19W; Q139X(rare)
R46L; L253F; A443T; E670G
Associated Phenotype(s)
Diabetes, Obesity, Hypertension,
Dyslipidemia
Dyslipidemia
Dyslipidemia, Hypertension
Dyslipidemia
Dyslipidemia
Dyslipidemia
Dyslipidemia
E23K
Diabetes
rs12255372 and rs7903146
Arg16Gly; Gln27Glu
N363S
rs7566605
rs3091244
G-308A
V103I
M235T; T174M
Gly482Ser
Diabetes
Hypertension, Obesity
Obesity
Obesity
Metabolic syndrome, Hypertension
Obesity, Metabolic syndrome
Obesity
Hypertension
Obesity, Diabetes
A98V (rare)
I/D promoter polymorphism
Trp64Arg
G10976A
-675 4G/5G
Diabetes, Obesity
Diabetes
Obesity; Metabolic syndrome
Obesity
Metabolic syndrome
K121Q
Diabetes, Obesity
A1166C
T-3892C (proxy for I/D)
C677T
Hypertension
Hypertension, Diabetes
Hypertension, Diabetes
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CARe Pilot Phenotypes
CSSCD
SOURCE: the CARe Portal
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CARe Phase Two
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All 50,000 CARe samples
“All” phenotypes eligible
Illumina IBC Chip (version 2)
Genotyping projected to begin Spring 2008
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Design of IBC SNP Panel
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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%)
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Combined effort : 210,000 samples to be scanned
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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
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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
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CARe Phase Three
• >10,000African American samples from CFS, ARIC,
JHS, MESA and CARDIA
• “All” phenotypes eligible
• Affymetrix 6.0
• Genotyping in progress
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CARe Projected Timeline
DNAs shipped to Broad
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
2008
Candidate Gene Genotyping
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Proposed CARe Workflow
ARIC
CSSCD
CARDIA
FHS
CFS
CHS
JHS MESA SHHS
DNA
Phenotypes
Broad
QC’d
Genotypes
Analysis
Engine
Standardized
Phenotype Data
Working
Groups
Harmonized
Phenotypes
Initial
Results
CARe
Portal
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Proposed CARe Workflow and 15 “High Priority Phenotype” Working Groups
ARIC
CSSCD
CARDIA
FHS
CFS
CHS
JHS MESA SHHS
DNA
Phenotypes
Broad
QC’d
Genotypes
Analysis
Engine
Initial
Results
CARe
Portal
Standardized
Phenotype Data
Working
Groups
Harmonized
Phenotypes
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
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CARe High Level Strategy
Trait 2
Trait 3
Trait 4
Cohorts
Trait 1
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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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