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MESA Genetics

This document provides an overview of the activities of the MESA Genetics Committee, including early SNP genotyping efforts, candidate gene projects, and collaborations with other NIH/NHLBI cohorts. It also discusses the MESA Family project and the status of MESA Candidate Gene studies. Additionally, it highlights other MESA Genetics projects, both completed and ongoing, as well as proposed projects.

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MESA Genetics

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  1. MESA Genetics MESA OSMB Meeting March 17, 2009 Dr. Rotter Dr. Rich

  2. MESA Genetics Activities OVERVIEW • MESA Genetics Committee • MESA Family • Early SNP genotyping • Candidate gene efforts funded by MESA Family • Other candidate gene projects • NHLBI genotyping initiatives • CARe • MESA-SHARe • SEA: SNPs and the Extent of Atherosclerosis • Other Collaboration Opportunities

  3. MESA Genetics Committee • Basic Charge: Provide a mechanism for coordinating, providing expert advice and resources for all MESA genetics activities • Membership: • Jerome Rotter (Chair) • Steve Rich • George Papanicolaou • Russ Tracy • Bruce Psaty • Wendy Post • David Herrington • David Siscovick • Mike Tsai • Graham Barr • Dick Kronmal • Donna Arnett • Craig Johnson

  4. MESA Genetics Committee • Coordination with other MESA Committees • Review of genetics ancillary proposals • Genetics P&P committee (separate but reviews manuscripts) • Expert liaison to other groups • NIH/NHLBI cohorts and efforts • Other genetics oriented scientific interests

  5. MESA Family • Progress, design, and Linkage resultsdescribed during scientific presentation

  6. MESA Family II • Primary Rationale of MESA Family II is to take advantage of the major strength of having: • GWL (genome wide linkage) • GWA (genome wide association) • Due to anticipated funding constraints, MESA Family II is being considered in 2 parts • Laboratory study with additional genotyping and bioassays • New phenotypic measures in MESA Family Cohort • Emphasis on Exam 5 subclinical disease measures • Emphasis on prior MESA Classic measures not currently collected in MESA Family • Events surveillance continues for MESA Family participants enrolled in MESA Air

  7. MESA Candidate Gene Status • Performed in ~2,880 MESA Classic subjects • 720 from each of the 4 ethnic groups • Including well-phenotyped “MESA 1000” • Total of 232 candidate genes genotyped • Two Panels of 1536 markers each (~3,000 SNPs total) • Illuminagoldengate custom 1536 panel (bead array) • CG selection based on Investigator recommendation • Marker selection based on • Platform considerations • Haplotype block considerations • + ~200 AIMs • Data distributed via “Gene Pages” • www.MESAgene.org (access granted via CC) • Phenotypes, exposures, and genotypes

  8. MESA Candidate Gene Status • Publication & Presentation status • 49 manuscript proposals • 7 publications or approved pen drafts • 19 approved/presented scientific meeting abstracts • Analyses • Hypotheses driven • Epidemiologic approach • Investigate association of markers in a specific gene/ROI with phenotype • Typically analyzed by author or designated analyst • Candidate Wide Association (CWAS) • Data mining approach • Investigate association of all genotyped markers with a specific phenotype • Typically analyzed by the UVA group (Joe Mychaleckyj)

  9. Pheno 1 Pheno 2 CWAS Approach Phenotype Class File Eg ECG N phenotypes 1001 12 2.41 4.77 1002 5.32 2.99 1003 6 1.69 4.13 1004 25 3.04 2.87 1001 AA GT AA CC CT 1002 AA GG AT CC CT 1003 AG GG AA CC CC 1004 AA GG AA CT CT Master Genetics File Pheno 1 Pheno 2 Pheno 3 SNP1 -0.93 SNP2 0.87 SNP3 1.10 SNP4 0.97 SNP1 1.22 SNP2 1.02 SNP3 -3.1 SNP4 -0.7 SNP1 1.34 SNP2 1.22 SNP3 0.61 SNP4 0.65 CWAS - 1 per phenotype . . . etc SNP106 SNP107 SNP108 SNP106 SNP107 SNP108 SNP106 SNP107 SNP108

  10. CWAS Example: Association Plots

  11. MESA Candidate Gene Plan • Replication (same SNPs) using the remainder of the MESA cohort • Additional genotyping (new SNPs) in existing genes/genetic regions • New candidate genes/regions • Validation of non-MESA findings • New ancillary proposals

  12. Other MESA Genetics Projects (Completed)

  13. Other MESA Genetics Projects (Ongoing)

  14. Other MESA Genetics Projects (Proposed)

  15. NHLBI SNP Genotyping and MESA • Candidate gene Association Resource • Collaborative (genotyping and analyses) • Includes 9 NHLBI cohort studies and Broad Institute CC • ~70 manuscript proposals from 14 working groups • Phase 1: PILOT • 35 SNPs (sequenom) • ~50,000 DNAs from all 9 CARe Cohorts • Limited phenotypes (hypertension) • Manuscript in progress • Phase 2: Candidate Gene Study • Illumina iSelect – IBC Chip • ~49,000 SNPs covering ~2,100 genes • ~50,000 DNAs from all CARe Cohorts

  16. NHLBI SNP Genotyping and MESA • Candidate gene Association Resource • Collaborative (genotyping and analyses) • Includes 9 NHLBI cohort studies and Broad Institute CC • ~70 manuscript proposals • Phase III: Genome Wide Association (GWAS) • Affymetrix Genome-Wide Human SNP Array 6.0 • ~1,000,000 SNPs (plus CNVs) typed • ~11,000 AFA DNAs • ARIC, CARDIA, Cleveland Family, JHS, & MESA

  17. NHLBI SNP Genotyping and MESA SHARe (SNP Health Association Resource) • Extends genome wide SNP genotyping to non-AFA MESA Classic • Includes MESA Air New Recruits and MESA Family Cohort • ~8,500 total participants • Affymetrix Genome-Wide Human SNP Array 6.0 • ~1,000,000 SNPs (plus copy number variants) • CARe AFA GWA will be merged into the MESA-SHARe database • Approval status: Centers have obtained IRB approval. Reviewing impact of NIH data sharing policy • Contractual arrangements March-April 2009 • DNA shipping April-May 2009 • Proposed contract issue date June 1st, 2009 • Genotyping Summer 2009

  18. NHLBI SNP Genotyping and MESA • NIH GWAS Data Sharing Policy • Changes to Data Access Policy and Procedure • Institutional proposal review redefined • Institutional Signing Official signature on Data Use Certification • IRB review not a requirement but may still occur (at ISO discretion) • ERA Commons account required • Data security Policy enhanced to comply with dbGaP Best Practices • Non-US institutions are not differentiated from US institutions • Clarification that commercial use limited to data where participants explicitly consented to commercial use • MESA-SHARe IRB approval status • FC and CC IRBs have approved • MESA Family and Air Centers expect approval next week

  19. SEA: SNPs and the Extent of Atherosclerosis • Collaborative effort between PDAY and MESA • PDAY (Pathobiological Determinants of Atherosclerosis in Youth) • Autopsy study (violent death) of raised arterial lesions • 15-35 year old Caucasians and African Americans • Phase 1: PDAY case-control pooled genotyping (2.4M SNPs) • Phase 2: PDAY individual genotyping (120K SNPs) • Phase 3: MESA Classic cohort individual genotyping (~3,000 SNPs, IMT) ID Refine Confirm

  20. Other Collaboration Opportunities • Consortiums that combine Cohorts across phenotypes • CHARGE • Consortiums than focus on one class of phenotypes • DIAGRAM (Diabetes) • MAGIC (Glucose, insulin) • GIANT (Height, weight, adiposity) • GLOBAL LIPIDS • GLOBAL BP GEN • GLOBAL QT

  21. CHARGE Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

  22. Rationale: Power for binary outcome

  23. Origins and goals of CHARGE • Incentives for collaboration • Need for large samples • Importance of replication • Conduct of high-quality analyses that produce reliable and valid findings across multiple common phenotypes in an efficient and timely fashion Psaty BM. Circ Cardiovasc Genet 2009; 2: 73-80.

  24. CHARGE eligibility and cohorts • CVD/Aging cohorts with GWAS data • CHS, FHS, AGEIC, AGES, Rotterdam • Others: ?MESA, CARDIA, HealthABC • Population-based cohort studies • Similar data collection methods • Multiple measures of risk factors and subclinical disease over time • Long-term follow-up of events

  25. CHARGE organization • Voluntary federation of cohort studies • Each with many investigators, traditions, and previous collaborations • Meta-organization of complex studies • Research Coordination Committee • Analysis and Genotyping Committees • Phenotype specific working groups • Develop plans/paper proposals, authorships • Adapt “central” analysis plan, timing for data sharing • Plan for follow-up genotyping, other collaborations

  26. Selected CHARGE results Phenotype New Loci, N Journal Uric acid 3 Lancet 2008;372:1953 ECG QT interval 5 Nat Genet, in press Blood pressure 10 Nat Genet, in press Fibrinogen 3 Circ CV Genet, in press Stroke 1 N Engl J Med, in press Nine other papers under review

  27. GWAS data in CHARGE cohorts AGES ARIC CHS FHS RS N 3,219 11,433 3,865 8,482 10,958 Age, yr 77 54 72 55 65 % women 58 55 61 53 58 % white 100 77 85 100 94 SNPs, k 325 869 307 502 531 Total, m 2.53 2.84 2.54 2.54 2.54

  28. Options: interaction of MESA with CHARGE • Currently MESA could serve as a replication cohort • replication decided by working group and MESA • Once the MESA-SHARe GWAS is completed • MESA can apply to be a full CHARGE consortium member cohort

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