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Genetics Committee Report

This report provides an update on the current status of the candidate gene study and outlines the next steps for future genotyping efforts. It includes information on the CWAS, MESA Genetics P&P, replication efforts, and abstract presentations.

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Genetics Committee Report

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  1. Genetics Committee Report MESA Steering Committee Meeting Wednesday February 27, 2008

  2. This evening, Maryland meeting room 5:30-6:30 CWAS Working Group • Details of sample results 6:30-7:30 AIMs Working Group • Discussion of adjustment methods 7:30-8:30 Phenotypes discussion • Approaches to CAC • Adjustment for underlying disease 8:30-9:30 Genotyping Subcommittee • Details of future genotyping activities

  3. Outline • CWAS • Current status for candidate genes and Next steps for future genotyping efforts • MESA Genetics P&P • MESA Family Report

  4. Candidate-Wide Association Study (CWAS) • CWAS includes: • One phenotype – all candidate genes analysis • Novel statistical approaches that consider multiple genes, multiple phenotypes, and multiple interactions • CWAS uses: • All 232 candidates and ~3000 SNPs • Single phenotypes • CWAS committee identifies: • Most highly associated SNPs within ethnic groups • Authors to write up the results

  5. CWAS Example: Association Plots

  6. CWAS Timeline • Condensed timeline • March 1, 2008, opening of CWAS shop • Accepting draft concept proposals • Distributing data • June 1, 2008, CWAS manuscript proposals due • August 1, 2008, CWAS pen drafts • CARE coming soon thereafter! • This timeline has been reviewed and approved by the Genetics Committee

  7. Outline • CWAS • Current status for candidate genes and Next steps for future genotyping efforts • MESA Genetics P&P • MESA Family Report

  8. Candidate Gene StudyCurrent Status • Performed in ~2880 MESA Classic subjects • 720 from each of 4 ethnic groups • Including well-phenotyped “MESA 1000” • Total of 232 candidate genes genotyped • Two Panels of 1536 markers each • Data distributed by MESAgene.org, GenePages • Currently 43 paper proposals

  9. 1st replication effort In the ~4000 remaining MESA CA, AA, HA subjects “interesting” findings from within the 43 paper proposals “top hits” from some/many CWAS-phenotype analyses AIMs and new genes, if funding allows Future genotyping efforts 2nd, 3rd replication of additional existing findings (in ~4000) Additional genotyping in interesting regions (in 2880) New genes/regions and new/existing Ancillary Studies (in some or all MESA subjects) Candidate Gene StudyNext Steps

  10. 1st Replication Genotyping Run • In ~4000 remaining MESA subjects • 384 or 768 SNP run, depending upon available budget • If 384 run, then½ SNPs allocated to important SNP findings from candidate gene paper proposals½ SNPs allocated to top CWAS findings • If 786 run, theninclude AIMs and new genes/regions (e.g. 9p21)as well as candidate gene and CWAS SNPs

  11. 1st Replication Genotyping Run • April 1 deadline for submission of candidate gene SNPs for replication • Recommend only “important” SNPs • Submitter must provide justification and documentation of “importance” for each SNP • If adding SNPs not previously genotyped, submitter must provide really good justification

  12. 1st Replication Genotyping Run • May 1 deadline for selection of top CWAS SNP hits for replication • Definition of “top” will depend upon number of SNPs in the genotyping panel • Subcommittee within Genetics Committee will write selection algorithm • Submitters must have approved concept proposal

  13. 1st Replication Genotyping Run • Submissions will be reviewed by Genetics Committee considering uniqueness of findings, particularly pertaining to • Ethnic group • Phenotype • Exposure • GOAL: submit Illumina order by late-May, start genotyping July/August

  14. Future Genotyping Efforts • Replication (same SNPs) using the remainder of the MESA cohort • Additional genotyping (new SNPs) in existing genes/genetic regions • New candidate genes/regions • Ancillary Study Proposals that wish to make use of the MESA genotyping facilities

  15. 1st replication effort “interesting” findings from within the 43 paper proposals “top hits” from some/many CWAS-phenotype analyses AIMs and new genes, if budget allows Future genotyping efforts 2nd, 3rd replication of additional existing findings Additional genotyping in interesting regions New genes/regions and new/existing Ancillary Studies Candidate Gene StudyNext Steps

  16. Outline • CWAS • Current status for candidate genes and Next steps for future genotyping efforts • MESA Genetics P&P • MESA Family Report

  17. MESA Genetics P&P • 43 approved paper proposals 1 penultimate draft approved 1 penultimate draft in revision and review process 41 papers in progress • 0-3 months (from approval) 14 • >3-6 months 13 • >6-9 months 9 • >9-12 months 5 • >12 months 0 Counts as of February 15, 2008

  18. MESA Genetics P&P • Abstracts 2 abstracts presented at American Society of Human Genetics meeting (Oct. 2007) 5 abstracts will be presented at the AHA 48th CVD Epi meeting (Mar. 2008) 1 abstract will be presented at the American Thoracic Society Meeting (May, 2008) Counts as of February 15, 2008

  19. MESA Genetics P&P Counts as of February 15, 2008

  20. Outline • CWAS • Current status for candidate genes and Next steps for future genotyping efforts • MESA Genetics P&P • MESA Family Report

  21. Major Goals Achieved • Recruit and phenotype MESA families • Completed • Including the addition of de novo families • Family linkage study • Proposed using Mammalian Genotyping Service • Performed using Illumina SNP linkage chip • Candidate gene study (MESA Classic) • Proposed 80 markers in 10 genes • Performed 3000+ markers in 200+ genes plus ancestral informative markers (AIMs)

  22. MESA Family Timeline • Candidate gene efforts are on track • Family linkage was delayed a year due to change in genotyping source • No cost extension anticipated thru June 2009

  23. MESA FamilySibpair AccrualExceeded Goal of 2,700 by 12% 1 Probands include MESA Classic Probands only 2 Sibling visits also include classic participants who are also siblings and de novo recruited participants

  24. MESA FamilyPhenotyping and Sample Collection(as of Jan 2008)

  25. MESA Family vs. MESASummary of Subclinical Measures

  26. Genome-wide Linkage Study • Genotyping with Illumina Infinium HumanLinkage-12 Beadchip completed • 12 samples per chip • 6,090 SNPs per sample • Call rates ≥ 98% • Data cleaning, pedigree checking in process

  27. MESA Family Upcoming Activities • Linkage analyses • Follow-up genotyping of linkage peaks • Candidate gene and CWAS analyses and papers • Follow-up genotyping of candidate genes • Participation in MESA SHARe

  28. Outline • Current status for candidate genes • Next steps for further genotyping • CWAS • AIMs • Genetics P&P

  29. Candidate-Wide Association Study (CWAS) • Analysis • Standard process, pre-computed, available • Filtering on MAF > 0.05 • Additive model within ethnic group • Age, sex, center-adjusted • Standard materials • Counts per genotype • MAF, HWE tests, for each SNP • Q/Q plots, graphical summaries of significance per trait • Interpretation • Interesting results demand replication • Further analyses for refinement of results • Cautious evaluation of significance

  30. CWAS Topics Already Discussed Yongmei Liu CT CAC & machine learning techniques (Interactions) - Approved Michele Sale CT CAC & prognostic modeling - Approved Walter Palmas Hypertension and arterial pulse waveform Mark Goodarzi Insulin resistance (HOMA, fasting glucose and insulin, diabetes) Kent Taylor IMT Nancy Jenny IL6 Mary Cushman Ddimer Ida Chen Metabolic syndrome Donna Arnett LV mass by MRI Kurt Daniel Heart size by CT Jing Ding/Jeff Carr Pericardial fat by CT Xiuxing Guo Steatosis Sanjiv Shah Cardiac Contractility Joe Mychalekcyj Renal Steve Rich Fatty acids Lynn Hedrick HDL & components Wendy Post LDL, Trig, cholesterol Shannon Rhodes Statin response Graham Barr Lung density Many other opportunities… Topics as of February 15, 2008

  31. CWAS: Encourage, Invite • Solicit recommendations for investigators for potential papers • Contact those with interest in phenotype • Contact those with interest in genotype • Invitation to assemble a team and to submit a paper proposal on that specific gene/phenotype combination • Rapid response • Analysis • Interpretation • Publication • Replication

  32. Future Genotyping Efforts Populations Available • Original genotype cohort (~2,880) • Remainder of the cohort (~4,000) • Entire cohort, for new genes/loci/SNPs (~6,800) • Subjects with specific phenotype data (e.g. MESA Lung, MESA Inflammation)

  33. Future Genotyping Efforts Requirements by type of application

  34. Future Genotyping Efforts Review process by type of application

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