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MESA Genetics

MESA Genetics. March 8, 2011 Jerome I. Rotter. MESA Genetics Meeting Agenda. Overview of MESA Genetics Activities - Rotter MESA SHARe Status - Rotter HeartGo/ESP Status - Rich MESA Aortic Valve Calcium - Campbell/Post

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MESA Genetics

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  1. MESA Genetics March 8, 2011 Jerome I. Rotter

  2. MESA Genetics Meeting Agenda Overview of MESA Genetics Activities - Rotter MESA SHARe Status - Rotter HeartGo/ESP Status - Rich MESA Aortic Valve Calcium - Campbell/Post Genetic Contributions Beyond GWAS in Working Groups and Scientific Opportunities– Rotter/Rich

  3. MESA Genetics Overview There are now 5 updates of MESA SHARe phenotypes, and we have added the Care IBC candidate gene data as well. MESA SHARe Newsletter was distributed to participants We have now expanded to 10 MESA SHARe analytic sites The third in-person MESA SHARe meeting was held on 2/9/11 in Boston, preceding the meeting of the CHARGE (Cohorts for Heart and Aging Research in Genetic Epidemiology consortium). The focus was on the “Multi-ethnic in MESA.” 20 MESA SHARe Working Group Candidate Analysis Committees have submitted 41 approved publication proposals. 1 paper has been published (Song et al, Nature, 12/16/10, 468:933-39), and 3 pen drafts have been submitted.

  4. MESA Genetics Overview We have integrated MESA into a large number of consortia, collaborating with the following studies and consortia: CHARGE, ICBP, GIANT, Global Lipids, MACAD, PRIMA, GENEVA, CARe, NOMAS, CARDIA, SPIROMETA, HealthABC, SUNLIGHT, CKDGen, FIND, WHI, Family Heart Study, Genestar, Diabetic Heart Study, Framingham, AGES, ARIC, MEDIA, IRAS Family, GUARDIAN, Jackson Heart Study, African-American Coronary Calcium, African-American Quantitative T2D Traits. The MESA CNV (copy number variant) Study utilizing MESA Family is proceeding with delivery of all samples and completion of the design of the custom arrays, with delivery of the manufactured arrays planned for March 2011 and data available for April 2011. MESA continues its contributions to the NHLBI Exome Sequencing project, as part of the HeartGO effort, which includes 6 NHLBI cohorts. Over 2500 of the planned 7500 exomes have been sequenced, and data analysis is now proceeding.

  5. MESA Genetics Overview • The biggest challenge is both encouraging and keeping track of the participation of MESA and MESA SHARe investigators in the multiple MESA SHARe working groups, the multiple collaborative GWAS groups such as CHARGE, and the multiple groups of the ESP. • This is accomplished through the network of the MESA SHARe working groups, with coordination by the • MESA Genetics Committee (Chair Rotter, Co-Chair Rich) • MESA SHARe Analytic Committee (Chair, Mychaleckyj) • MESA Genetics P&P (Chair, Post) • MESA SHARe Executive Committee (Co-Chairs, Papanicolaou and Rotter) • HeartGO Steering Committee (Chair, Rich) • Coordinating Center

  6. MESA Genetics Activities • MESA Genetics Committee • MESA Family • Early SNP genotyping • Candidate gene efforts funded by MESA Family • Other candidate gene projects • Large Scale Genotyping • CARe • SEA: SNPs and the Extent of Atherosclerosis • MESA-SHARe • Other Genetic Initiatives • Epigenomics • MESA CNV • Human Exomics • MESA Leukocyte

  7. MESA SHARe UpdateJerry Rotter March 8, 2011 Jerry Rotter

  8. MESA SNP Health Association Resource (SHARe) Progress Report • MESA SHARe extends genome wide SNP genotyping to non-AFA MESA Classic, MESA Family, and MESA Air New Recruits using Affymetrix Genome-Wide Human SNP Array 6.0 (1M SNPs plus CNVs) • 8402 participants consented to genotyping, 8298 passed QC filters and are available on dbGaP Study Timeline

  9. MESA SNP Health Association Resource (SHARe) Progress Report • Imputation data for all four ethnicities distributed by CC and UVA July 2010 using HapMap 1&2. Second generation dataset using HapMap 3 and 1000 Genomes is being packaged for distribution to approved SHARe Analytic Sites. • Participant newsletter designed to engage and educate MESA participants about genetics studies was sent to participant homes in Fall 2010. • Next in-person meeting will be at September 2011 Steering Committee Meeting in Washington DC. • dbGaP Update Schedule:

  10. MESA SHARe Phenotype Data • -MESA Exams 1-4 • -Events • -MESA Family Exam • -MESA Air New Recruits Exam • -MESA Lung • -Aortic CT • -Testosterone • Version 2 MESA SHARe Update (released May 2010) • -Pericardial Fat Update • -Sphingomyelin • -Testosterone • -Adiponectin • -FMD • -Abdominal Aortic Calcium • -Cardiac MRI Update (E1-4) • -Atrial fibrillation events • Version 3 MESA SHARe Update (Released Aug 2010) • -MESA Air IMT • -Medications Update • -GFR with the CKD-epi equation • -MESA Eye: CRAE/CRVE Retinopathy All phenotypes used for GWAS must be posted on dbGaP Version 1 Phenotype datasets posted on dbGaP include:

  11. MESA SHARe Phenotype Data • -Type 1 Diabetes indicator • -Events through FU8 • -Inflammation • -Nutrients • -BNP • -MESA Stress – cortisol • -IL-10 • -MESA Lung CT • -NAFLD CT • - MESA Eye Refraction • - ECG p-wave data • MESA Lung CT update • Leptin • - Consent Update • IL2R and sTNFaR1 • MESA Air distance to roadway • Version 4 MESA SHARe Update (Released Nov 2010). • Version 5 MESA SHARe Update (Released Feb 2011) • Version 6 MESA SHARe Update (planned for May 2011)

  12. MESA SHARe Approved Analytic Sites Approved MESA SHARe Analytic Sites have access to derived MESA SHARe datasets, including PCAs and imputation. • Cedars-Sinai Medical Center (PI: Jerome Rotter, MD) • University of Virginia (PI: Stephen Rich, PhD) • University of Washington (PI: Richard Kronmal, PhD) • Wake Forest University (PI: Gregory Burke, MD, MSc) • Johns Hopkins University (PI: Wendy Post, MD, MS) • University of California, San Diego (PI: Christina Wassel, PhD) • University of Michigan, Ann Arbor (PI: Yan Sun, PhD, MS) • University of Texas (PI: Jennifer Nettleton, PhD) • Loyola University (PI: Holly Kramer, MD, MPH) • University of Vermont (PI: Russell Tracy, PhD) 18 additional groups outside of MESA have applied for and gained access to MESA SHARe data.

  13. MESA SHARe Phenotype Working Groups • 20 MESA SHARe Phenotype Working Groups actively meet. • Since April 2010, 41 publication proposals, and 3pen draft were submitted from 16 different Phenotype Working Groups and SHARe Committees • 19proposals use standard analysis plan developed by MESA SHARe Analysis Committee, 18 follow analysis outlined by consortia, and 4 use non-standard analysis as defined by the Working Group. • 1 paper published (Goodarzi, Nature Dec 16 2010: 468:933-41) • Includes collaborations with CHARGE, ICBP, MACAD, PRIMA, GENEVA, CARe, NOMAS, Type 2 DM Consortium, CARDIA, SPIROMETA, HealthABC, SUNLIGHT, CKDGen, FIND, WHI, Family Heart Study, Genestar, Diabetic Heart Study, Framingham, AGES.

  14. MESA SHARe Phenotype Working Groups

  15. HeartGo/ESP StatusSteve Rich March 8, 2011 Jerry Rotter

  16. HeartGo/ESP Status Steve to provide In the Early MI project: 0 samples were sent to the Broad; In the LDL project: 0 samples were sent to Seattle; In the Blood Pressure project: 46 samples were sent to the Broad, all passed initial QC, all are being sequenced; In the Stroke project: 12 sample was sent to the Seattle, all passed initial QC, all have been successfully sequenced; In the DPR (ESP version of a random sample): 50 samples were sent to the Broad, all passed initial QC, 32 have been successfully sequenced and the rest are being sequenced; also, 51 samples were sent to Seattle, all passed initial QC, 26 have been successfully sequenced and the rest are being sequenced. So the summary is: A total of 159 samples sent; A total of 159 passed initial QC; A total of 0 are known to have failed in sequencing; A total of 58 have been successfully sequenced; A total of 101 are still in the sequencing pipeline; ARIC    HeartGO DPR Cohort              pending CARDIA  HeartGO DPR Cohort              54 CHS     HeartGO DPR Cohort              102 FHS     HeartGO DPR Cohort              66 JHS     HeartGO DPR Cohort              26 MESA    HeartGO DPR Cohort              101 WHISP                                           406 Total to date: 755; ARIC samples pending.

  17. MESA Aortic Valve Calcium Wendy Post/Catherine Campbell March 8, 2011 Jerry Rotter

  18. MESA Aortic Valve Calcium

  19. Genetic Contributions Beyond GWAS in Working Groups and Scientific OpportunitiesJerome I. Rotter and Stephen S. Rich March 8, 2011 Jerry Rotter

  20. MESA Assets for Future Genetic Studies 1. Our Cohort – MESA/MESA Family/MESA Air • DNA • Cryopreserved cells • Cell lines in MESA Family • Serum/plasma • Lots and lots of phenotypes • Exposure data

  21. MESA Assets for Future Genetic Studies 2. Genotyping • GWAS on all – MESA SHARe • IBC Chip on MESA Classic (from CARe) • GoldenGate (x2) on 2,880 of MESA Classic • Metabochip on part of MESA Classic African Americans • Genotyping from SEA on MESA Classic • Linkage markers on MESA Family 3. Copy Number variant analysis on MESA (on-going)

  22. MESA Assets for Future Genetic Studies 4. Exome sequencing on a portion of MESA Classic as part of HeartGo/ESP (ongoing) 5. Epigenomics on a portion of MESA Classic (ongoing) 6. SEA project – relation with PDAY 7. MESA Inflammation – stored cell subsets on a portion of MESA Classic 8. Data from the many ancillary studies 9. Participation in many GWAS consortia, most notably CHARGE and COGENT, (but many others)

  23. MESA Assets for Future Genetic Studies 10. Existing MESA Infrastructure • Field Centers • Coordinating Center • Central Lab • Reading Centers • MESA Air • Genetic Centers • MESA SHARe Analytic Centers

  24. Possible Future Directions for MESA Genetics 1. Extend/Renew MESA SHARe Rationale: Maximize investment. Many of the working groups are very active, but CHARGE and CARe experience has shown that one needs 5-6 years to maximize initial productivity. 2. Exome Sequencing in all of MESA Family Rationale: Theoretical work has indicated that study of families increases the identification (and confirmation) of rare variants. MESA Family is rather unique in having African American and Hispanic Americans with subclinical CVD phenotypes.

  25. Possible Future Directions for MESA Genetics 3. Extend sequencing (i.e. expand HeartGo) A. Exome sequencing in all of MESA B. Whole genome sequencing in all of MESA Rationale: The search for rare variants requires a large sample size for each of the MESA traits. Since the correlation structure of the traits is broad, to access all traits, one needs to sequence virtually everyone. 4. MESA 1000/MESA Inflammation - Proceed to extend expression and methylation to cell subsets. Rationale: Bank of live subsetted cells available, related to the MESA phenotypes.

  26. Possible Future Directions for MESA Genetics 5. Induced Pluripotent Stem Cells(iPSCs) Rationale: This will allow for differentiation into differentiated cells, facilitating functional studies, especially related to genotyping and/or sequencing data. Theoretically, any live cell source (e.g. skin biopsy, cryopreserved cells, hair follicles, cell subsets, immortalized cell lines). 6. Create immortalized cell lines on all MESA and MESA Air (already done on MESA Family) Rationale: Allows functional studies; much more cost effective than iPSCs.

  27. Possible Future Directions for MESA Genetics 7. Gene Environmental Influences – study all infectious agent antimicrobial antibodies Rationale: Explores the infection disease burden hypothesis of atherosclerosis and aging in the context of MESA genetics. 8. Microbiome and Adiposity Rationale: Relation of microbiome to adiposity as measured in the whole body (BMI) and in fat depots (subcutaneous, visceral, liver, pericardial), together with inflammatory markers.

  28. Possible Future Directions for MESA Genetics 9. Proteomics 10. Metabolomics 11. MESA Offspring study Rationale: Identifying phenotypes earlier in the course of disease development, taking advantage of well-phenotyped parents.

  29. Next slide is for MESA SC – Genetics Update

  30. Agenda for MESA Genetics at SC Overview of MESA Genetics Activities - Rotter MESA SHARe Status - Rotter HeartGo/ESP Status - Rich MESA Genetics P&P Update - Post

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