MESA Genetics Report

1. MESA Genetics Report September 14, 2010 Jerry Rotter

2. Genetics Report Outline MESA SHARe MESA CNV MESA Exome/HeartGO MESA Genetics P&P Other Business

4. 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 • CARe AFA GWA data were merged into the MESA-SHARe database in dbGaP Study Timeline

5. 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 expected October 2010. • Participant newsletter designed to engage and educate MESA participants about genetics studies will be sent to participant homes Fall 2010. • Planning underway for next in-person meeting one day before February CHARGE Meeting in Boston.

6. 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 • -BNP • -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 All phenotypes used for GWAS must be posted on dbGaP Version 1 Phenotype datasets posted on dbGaP include:

7. MESA SHARe Phenotype Data • Version 4 Update planned for Oct/Nov 2010. • Nutrients • Events through FU8 • Inflammation • Type 1 Diabetes indicator • dbGaP Update Schedule:

8. 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) • University of Texas (PI: Jennifer Nettleton, PhD) 10 additional groups outside of MESA have applied for and gained access to MESA SHARe data.

9. MESA SHARe Phenotype Working Groups • 20 MESA SHARe Phenotype Working Groups actively meet. • Since April 2010, 25 publication proposals and 2 pen drafts were submitted from 12 different Phenotype Working Groups, including 3 each from Eye, AF/ECG, and Nutrition, and 7 from BP/Hypertension. • 9 proposals use standard analysis plan developed by MESA SHARe Analysis Committee, 11 follow analysis outlined by consortia, and 5 use non-standard analysis as defined by the Working Group. • 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.

10. MESA SHARe Phenotype Working Groups

11. MESA SHARe Phenotype Working Groups

12. MESA SHARe Phenotype Working Groups New!

13. Agenda

14. MESA CNV CNV

15. MESA Copy Number Variant (CNV)Progress Report CNV Examines the role of structural variants (insertions, deletions, copy number variants (CNVs), variable number of tandem repeats (VNTRs)) on risk of atherosclerosis and risk factors Structural variants difficult to characterize and genotype, as compared with SNPs (single nucleotide polymorphisms) Designing a custom array to include structural variants (8x60K Agilent array) As structural variants can be de novo or inherited, the most powerful design uses families (to track transmission of CNVs) MESA Family Study (~2100 participants, 595 families) will be used (328 African-American; 267 Hispanic)

16. MESA CNV Progress Report: Loci To Target Redundancy to remove Clusterable, untagged CNVs N=~1500 N=~1000 MAF>1% Unclusterable, but real CNVs N=~2000 Novel insertion Sequences (Venter) N= ~200 1000 genomes SVs N=~10,000 N=~5,000 not in WTCCC and assayable Filter: CEU, not-tagged Candidate/ interesting loci e.g., VNTR Functional elements in associated intervals N=~9500 N=6800 >50bp N=4500 >100bp 3 probes/element 10 probes/CNV ~10-15K probes ~20K probes ~2K probes ~10K probes ~100 probes ~13-20K probes ~1.4K probes Agilent control probes Array Design CNV ~60,000 probes

17. MESA Exome/HeartGO Exome

18. NHLBI Exome Sequencing Project (ESP) Report: Major Goals: 1) To discover novel genes and mechanisms contributing to heart, lung, and blood disorders by pioneering the application of next-generation sequencing of the human protein coding regions across racially and ethnically diverse, richly-phenotyped populations; 2) To establish robust methods to discover novel disease susceptibility genes by next generation sequencing and analysis of identified rare mutations; 3) To share these datasets, methods, and findings with the scientific community to enhance the diagnosis, management and treatment of heart, lung, and blood disorders Exome

19. NHLBI Exome Sequencing Project Report: Structure of the ESP Exome • Three cohort-based groups • Heart disease (HeartGO, S Rich) • Lung disease (LungGO, M Bamshad) • Women’s Health Initiative (WHISP, R Jackson) • Two sequencing centers • Broad Institute (BroadGO, S Gabriel/D Altshuler) • University of Washington (SeattleGO, D Nickerson) • Two additional GO components • CHARGE-S (E Boerwinkle, targeted sequencing) • WashUGO (T Graubert, cancer focus, whole genome seq)

20. NHLBI Exome Sequencing Project Report:HeartGO Structure HeartGO Coordination University of Virginia(S Rich, PI) CHS B Psaty R Tracy ARIC E Boerwinkle A Morrison CARDIA M Gross A Reiner FHS L Atwood C O’Donnell JHS H Taylor J Wilson MESA J Rotter W Post Requirements: IRB APPROVAL, 5ug DNA, GWAS guidelines HeartGO supports Labs, Coordinating Centers, and Genetic Counseling Exome

21. NHLBI Exome Sequencing Project Report: Events High FRS no MI Early-onset MI Established with ARRA funding Extremes of cardiovascular and lung phenotypes to be analyzed to enrich for genetic effects Early On-set Disease “Mendelianize” Traits-Compare extremes of trait distribution Rare, higher penetrant variants Also ischemic stroke (lacunar or atherosclerotic subtypes only) Example of design Exome

22. NHLBI Exome Sequencing Project Report: QTLs LOW BP LOW LDL HIGH LDL HIGH BP 100 in each tail x 2 ethnic groups MESA contributions BP: 48 stroke: 12 Deeply Phenotyped Reference DPR: 101 Exome

23. MESA in dbGaP

24. MESA Genetics P&P

25. Genetics P and P Published Genetics Manuscripts 8 In press 1 Approved Penultimate Drafts 11 (not accepted or published) Includes 2 GWAS consortium papers Approved Proposals (no approved pen draft) 72 MESA SHARe/Collaboration proposals 26(includes 2 approved pen drafts) Withdrawn Proposals 1

26. MESA SHARe paper proposals by working group (n= 26) Blood Pressure 7 Eye 3 LV Function/Structure 2 Adiposity 1 AF/ECG 3 Nutrition 3 Subclinical Atherosclerosis 2 Lipids 1 Diabetes 1 Fatty Acids 1 Renal 1 Inflammation 1

27. MESA SHARe • Proposals receive a “stream-lined” review. • Additional questions posed to help with review. • Will data from non-MESA cohorts or consortia be included in the manuscript? • Are you using one of the approved analytic plans? • Who is the analyst for your proposal? • What MESA SHARe working group is responsible for the phenotypes in your proposal? • Have you discussed the proposal with your working grou • Has the working group approved submission of this proposal? Sharon will send out Genetics P&P Guidelines and Checklist shortly

28. Consortium papers • Pen drafts receive expedited review which is focused on • whether MESA is properly represented • whether acknowledgements are correct • scientific comments should focus on major comments since these papers are reviewed by so many people. • Consortium proposals and pen drafts don’t require SC approval (information only)

29. CARe 147 approved paper proposals- listed in SC report. One published paper- design paper Publications chair- Jim Wilson MESA representative- Wendy Post Proposals and manuscripts not reviewed by MESA P and P

30. Genetics P and P membership Wendy Post (chair) Johns Hopkins University Stephen Rich (co-chair) University of Virginia Donna Arnett University of Alabama Xiuqing Guo Cedars Sinai Medical Center Spencer Huang Northwestern University Nancy Swords Jenny Blood Laboratory Yongmei Liu Wake Forest University James Pankow Minnesota Field Center Ken Rice Coordinating Center Michele Sale University of Virginia Special thanks to Sharon Fentiman-coordinating center

31. In Summary

32. Genetics Report Summary • MESA SHARe • MESA CNV • MESA Exome/HeartGO • MESA Genetics P&P • Other Business • Consents for iPSC • Other • SEA

34. MESA SHARe Participants by Cohort and Race Feb 2010, dbGaP Version 1

35. Approved non-MESA DARs for MESA SHARe Data Columbia University (PI: Ali Gharavi) Genetic studies of chronic kidney failure (CKD) University of California San Diego (PI: Jonathon Sebat) Cross disorder analysis of structural variants in multiple psychiatric diseases Neocodex (PI: Maria Saez) ARIC_RCV Harvard University (PI: Dennis Wall) Methods for analysis of biological process enrichment in GWAS data Indiana University – Purdue University (PI: Jennifer Wessel) Personalized Behavioral and Therapeutic Intervention for Coronary Artery Disease: Translating Genome-Wide Association Results into Early Intervention for Coronary Artery Disease

36. Approved non-MESA DARs for MESA SHARe Data University of North Carolina Chapel Hill (PI: Kirk Wihelmsen) CHAT: Convergent Haplotype Association Tagging Washington University (PI: Laura Bierut) Multi-ethnic study of addication Washington University (PI: Aldi Kraja) An integrative approach to study metabolic syndrome in human and animal models Duke University (PI: Jeanette McCarthy) Gene by sex interaction in metabolic traits St Jude Children’s Research Hospital (PI: Jun Yang) Genome-wide interrogation of SNPs associated with childhood acute lymphoblastic leukemia in diverse racial/ethnic populations

37. Committees • MESA SHARe Executive • Charge is to discuss workflow and timelines and discuss project and policy issues as needed (oversight mechanism) • MESA SHARe Analysis • Charged with: • Genotyping QC • Data sharing mechanisms and constraints for individual genotype and summary data; sharing with internal and external investigators (consortia) • QC algorithms • Support for Working Groups • MESA Genetics • Charge is to discuss policy, inform MESA investigators about genetics analyses and assign phenotypic priorities. • Major topics of discussion include • Phenotype Priorities • Working Group Organization • Participation with other GWAS consortia • MESA Genetics P&P • Revise genetics proposal template to accommodate the swift response necessary for large-scale collaborations

38. MESA SHARe Background & Timeline SHARe (SNP Health Association Resource) • Extends genome wide SNP genotyping to non-AFA MESA Classic • Includes MESA Air New Recruits and MESA Family Cohort • 8298 total participants • Affymetrix Genome-Wide Human SNP Array 6.0 • ~1,000,000 SNPs (plus copy number variants) • CARe AFA GWA merged into the MESA-SHARe database • DNA shipping July-Sept 2009 • Genotyping July-Sept 2009 • Data Cleaning and initial dataset preparation Oct 2009 - Feb 2010 • Post genotype and phenotype data to dbGaP Feb 2010 • First phenotype data update May 2010

39. MESA SHARe Phenotype Working Groups It is proposed that Writing Groups focus on 5 types of papers: Analysis of previously identified loci/SNPs, MESA-led, all ethnicities MESA unique phenotypes, full GWAS, MESA-led, all ethnicities Common Phenotypes, full GWAS, MESA-led or joined, non-white study groups Common Phenotypes, full GWAS, MESA-joined, white study group Common Phenotypes, Replication of top hits, MESA-joined

40. Data Sharing • How the process works • MESA is bound by the same rules as any other GWAS with data deposited at NIH/NCBI (dbGaP) • MESA investigator institution must approve submission of application to NIH DAC for access to data • To download data each center must fill out an application on the dbGaP website • The CC has provided a template dbGaP application • Exclusivity of GWAS data for MESA Investigators is for one year after data release on dbGaP • Outside investigators may download the data as available on dbGaP but cannot publish results until one year after initial release.

41. MESA SNP Health Association Resource (SHARe) Progress Report • 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 have genotype and phenotype data available on dbGaP • CARe AFA GWA data are merged into the MESA-SHARe database

42. 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 expected September 2010. • Participant newsletter designed to engage and educate MESA participants in relevant genetics studies will be sent to participant homes Autumn 2010. • Since April, 25 publication proposals (including 2 pen drafts) have been submitted from 12 different Phenotype Working Groups, including 3 each from Eye, AF/ECG, and Nutrition, and 7 from BP/Hypertension. • MESA SHARe Phenotype Working Groups are collaborating with more than 20 different consortia.

43. MESA CNV Progress Report: 1000 Genomes Structural Variants Discovered SVs SVs with assembled breakpoints Genotyped SVs SVs with genotypes and breakpoints CNV