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MESA Genetics Activities

MESA Genetics Activities. Report to MESA Steering Committee Jerome I. Rotter, MD February 8 th , 2006. MESA Genetics Activities. Update on MESA Family – includes Large Scale MESA Candidate Gene Analyses Individual candidate gene genotyping

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MESA Genetics Activities

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  1. MESA Genetics Activities Report to MESA Steering Committee Jerome I. Rotter, MD February 8th, 2006

  2. MESA Genetics Activities • Update on MESA Family – includes Large Scale MESA Candidate Gene Analyses • Individual candidate gene genotyping • Larger scale candidate gene genotyping - NHLBI’s Candidate-gene Association REsource (CARE) • Scale of MESA Genetics Projects • Human Subjects / Field Center Issues

  3. MESA Family Current Priorities • Recruitment and Enrollment • Candidate Gene Analyses • Analyses of the 1st half of the family cohort

  4. MESA Family Timeline

  5. MESA Family Sibpair accrual (FC combined)

  6. MESA Candidate Gene Genotyping Study • Conduct an association study of 2,880 MESA participants (parent study) • 720 randomly selected from each ethnic group of Caucasian-, African-, Mexican-, and Chinese-Americans • Include the well-phenotyped “MESA 1000” • Genotype 1536 SNPs in candidate genes proposed by MESA Investigators

  7. MESA Illumina Marker Panel Marker Set # SNPs Cardiovascular Candidate Genes 1439 Ancestry Informative Markers (AIMs) 97 Mean SNPs/gene 11.3 Max SNPs/gene 49 (VWF) Min SNPs/gene 1 (VEGFB, MRPL10, KCNH2, FLJ3116, DMGDH, C4orf9) TOTAL SNPs ASSAYED BY 1536 ILLUMINA

  8. MESA Candidate Gene Data Overview • 1440/1536 SNPs were successfully genotyped • 119 genes represented • 97 ethnic-specific markers • Only 6 DNA samples did not genotype.

  9. MESA Candidate GeneSummary of Genotyping Results Illumina reports: • Data quality was very high • DNA success rate unprecedented (for such a large project) • Being pleased with the locus conversion rate (higher than predicted) • Excellent DNA quality (aided in achieving the high locus success rate)

  10. Analysis of DuplicatesGenotyping Quality • Spike each of 32 (96 well) DNA plates plates with 2 duplicate samples = 64 in total • Illumina notified of duplicates (non-blinded) • Add an extra plate (#33) of 4 ethnicities x 23 duplicates = 92 duplicates • Illumina not notified that these were duplicates (blinded) • Total: 64 + 92 = 156 duplicate pairs of DNAs

  11. Analysis of DuplicatesIllumina Non-Blinded 64 x 1440 – 45 – 31 = 92,084 genotype pairs (less missing 1 or 2 genotypes) Remove and do not count: 1 pair of clearly non-identical samples, mismatch at 628 / 1439 SNPs total typed (lab error ?). One other single pair of genotypes do not match Non-blinded pair concordance rate = (92084 -*1439-1) /(92084 – 1439) = >99.998% *1439 not 1440 – 1 missing SNP genotypes.

  12. Analysis of DuplicatesIllumina Blinded 92 x 1440 – 138 – 32 = 132,310 genotype pairs (less missing 1 or 2 genotypes) Remove and do not count: 2 pairs of clearly non-identical samples: 717 / 1439 and 717 / 1438 SNPs mismatch (lab error?). 4 other genotype pair mismatches Blinded pair concordance rate = (132,310 -1438-1439-4) /(132,310 –1438-1439) = >99.996% *1438 not 1440 – 2 missing SNP genotypes.

  13. Candidate Gene Data Use and Publication Approach • Moratorium on candidate gene manuscript proposals (~3 months) • MESA and MESA Family Study investigators surveyed concerning gene and phenotype interests • If several interested in same gene and phenotype, P&P Committee will encourage the development of writing groups: • To delineate the hypotheses and models • To recommend number of manuscripts • To recommend authors • Should a candidate gene have no ‘champion’, it will be assigned to Investigator who recommended it

  14. Individual MESA Candidate Gene Genotyping: The Problem Issue Need to prioritize Transferring samples is inefficient a. Inefficient use of samples b. Significant work for central laboratory/genotyping center Efficiencies of combining genotyping, e.g. multi-plexing Investigators often need guidance - a. on how to comprehensively interrogate a gene b. which samples should be utilized to answer the question

  15. Individual MESA Candidate Gene Genotyping Proposal Proposal: Create a subcommittee of the MESA Genetics Committee to evaluate and approve individual candidate gene studies Proposed subcommittee: Mike Tsai (Minnesota, Chair), Don Bowden (Wake Forest), Kent Taylor (Cedars-Sinai) Prior Discussion/Buy-in: Genotyping groups, MESA Lab Committee representatives, Ancillary Study Committee representatives, Program Officers

  16. Large-scale genotyping of NHLBI cohortsCARE = Candidate-gene Association REsource • Subjects • 8 NHLBI Cohorts • ~50,000 subjects • Genotyping • 1700 genes • ~8-10 markers per gene • Steering Committee • Formed 1/25/2006 • Selects genes and markers • Selects phenotypes

  17. Large-scale genotyping of NHLBI cohortsCARE = Candidate-gene Association REsource 8 NHLBI Cohorts • Atherosclerosis Risk in Communities (ARIC) • Coronary Artery Risk Development In young Adults Study (CARDIA) • Cardiovascular Health Study (CHS) • Cooperative Study Sickle Cell Disease • Framingham Heart Study • Jackson Heart Study • Multi-Ethnic Study of Atherosclerosis (MESA) • Sleep Heart Health Study

  18. Scale of MESA Genetics Projects * Under discussion

  19. Contrasting MESA Genetics Projects vs. Large Scale Sequencing Characteristics of MESA Studies • All studies being conducted at the moment (or being considered) are association studies • Association studies ask the question whether common variations in or near a gene are associated with a trait/disease • Therefore information is obtained only regarding the traits under study, not for other diseases or traits Alternate Approach • Large scale sequencing completely interrogates specific genes • If these genes are associated with any known disease, then finding variants/mutations have a clinical implication

  20. Human Subjects Issue as a Function of Study Design

  21. Recent NHLBI RFI • RFI seeking comment on proposed creation and release of limited access datasets (LAD) which are to include large amounts of genotype and phenotype data. • Cleaned genotype data to be delivered to NHLBI within 6 months of creation • Data immediately available to LAD participants at that time. • One year moratorium on publication submission for LAD participants.

  22. Issues Raised by NHLBI RFI Data cleaning • Is 6 months adequate for large scale data cleaning Is 12 months sufficient for: • Knowledgeable study Investigators to conduct well thought out analyses • Sufficient academic reward for overall conduct of the study Confidentiality • Did the study subjects knowingly consent to a forensic equivalent genetic dataset? • Subject concerns • IRB concerns Negative impact on future cohort studies

  23. Possible Responses to NHLBI RFI • NHLBI encourages comments (due by March 8th) • Individual MESA and other Cardiovascular scientists should weigh in • When doing so, acknowledge the potential conflict of interest and/or emphasize scientific and human subject issues • Besides individual responses, propose a MESA Steering Committee response (drafted by MESA Genetics and appropriately revised by MESA Steering Committee)

  24. End

  25. MESA Family Sibpair Enrollment(as of 12/31/2005)

  26. Analyses in MESA Family First Half CohortWhat to do until the genes come? Heritability analysis Bivariate analysis

  27. Simple correlation & Bivariate analysis in MESA Family, Example Individual Sib1 Sib2 CAC IMT CAC IMT Simple correlation Bivariate analysis

  28. MESA Candidate Gene Selection • 267 candidate genes were initially proposed by MESA investigators, collated by DCC, and then ranked by MESA investigators • Further input by MESA laboratory and MESA Family Study Genetics Committee (294 genes) • List of 294 genes sent to Illumina • list of 60,293 SNPs returned with feasibility scores • tag SNPs identified, total 1,439 • List became final when SNP selection was complete

  29. Individual MESA Candidate Gene Genotyping Proposal (continued) Procedure: proposal would come to the Ancillary Committee and be routed to MESA Genetics, then to subcommittee Proposals allowed twice a year All genotyping will be done by “MESA-related” genotyping labs, e.g. Minnesota, Cedars-Sinai, Wake Forest, Vermont Analysis: Subcommittee to decide: Which site – e.g. Cedars-Sinai, Minnesota, etc… Which samples - 720 (one ethnic group) - multiple of 720, up to 2880 - 1000 (MESA 1000) - all Work with proposer as to number of markers required

  30. Individual MESA Candidate Gene Genotyping Proposal (continued) Ranking Subcommittee or whole committee would rank proposals • highly meritorious and rank within • meritorious and rank within • not approved Funding: There will be 2 categories of approved proposals One: Proposals that will be done “gratis” (supported by genotyping lab and/or MESA funds) Size/amount to be determined Two: Proposals that will be done with budget provided (e.g. supplies, technician time) Details to be worked out by subcommittee

  31. Genome Wide Association Studies • SNPs and the Extent of Atherosclerosis (SEA), David Herrington, PI • Genome wide association will be done in PDAY samples • 1st confirmation will utilize PDAY samples • 2nd confirmation will use MESA samples

  32. Genome Wide Association Studies • NIH RFA (to be released, due date 4/20/06) • MESA, with its 6000+ individuals, 4 ethnic groups, and quantitative phenotypes, is a very attractive venue for such studies • Ideally such a study would involve 3 stages • Stage 1: genome wide: 2000 subjects (all 4 ethnic groups) • From 250,000 to 500,000 markers • Stage 2: 1st confirmation large scale: 2000 subjects • From 20,000 to genome wide • Stage 3: 2nd confirmation: 2000 subjects • From 500 to 2,500 markers • However, the resources proposed to be provided by the RFA appear to be too limited for this scope

  33. MESA Large Scale Collaborations Queries: Dallas Heart Framingham Offspring Rochester Family Heart (ECAC) Concept: Devise arrangements for joint testing, or for confirming results seen in one population in the other

  34. MESA Large Scale Collaborations • Example • Epidemiology of Coronary Artery Calcification (ECAC) • Formerly Rochester Family Heart Study • Pat Peyser, University of Michigan, PI • Scientific Questions • The genetic basis of progression of CAC • ECAC has follow-up data, average 8 yrs (up to 13 yrs) • ECAC would like to interact (i.e. could MESA confirm candidate gene associations they will identify) • Issues for MESA • What does MESA want to do regarding this scientific question? • What interaction, if any, do we want with another group? • If yes, how would we want to structure it?

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