MESA Steering Committee Genetics Committee Update 1 MESA Genetics Overview Genetics Datasets Availability Update on Genetics PampP Return of Results Epigenetics NHLBI TOPMed program a WGS ID: 1045586
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1. April 20, 2017Jerome I. Rotter, MD and Stephen S. Rich, PhDMESA Steering CommitteeGenetics Committee Update1
2. MESA Genetics OverviewGenetics Datasets AvailabilityUpdate on Genetics P&PReturn of ResultsEpigeneticsNHLBI TOPMed program a. WGS b. Multi-Omics2
3. Genetics Datasets AvailabilityGenetic datasetAvailable w/MESA ID from CCAvailable w/SHARe ID from CCAvailable w/SHARe ID from dbGaPAffy 6.0NoYesYesCandidate Gene 1&2YesNoNoCARe IBC iSelectYesYesYes96 SNPYesYesNoMetabochipYesNoNoExome ChipYesYesYesExome SequenceYes YesYesEpigenomics methylationYesNoNoEpigenomics expressionYesNoNoSHARe Principal ComponentsYesYesNo1000 G ImputationNoYesNoPhenotype UpdatesYesYesYesWhole Genome SequenceIn progressTOPMed MESA ‘Omics- Methylation, Metabolomics, RNA SeqIn progress3
4. MESA Genetics P&P Summary AllSHAReProposals approved558416Pen Draft Pending (Proposals approved; pen draft not yet approved)275211Withdrawn4016Pen Draft approved240187Published146113Pen Draft approved; not yet published9877Pending Pen DraftPen Drafts not published0-3 months6153-6 months24146-9 months16119-12 months19712+ months210514
5. MESA Genetics Published Papers: RecentTitleMESA LeadJournalPub DateG 347: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.Alexis C. Frazier-WoodNat Genet.4/18/2016G 077: KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.Jennifer NettletonProc Natl Acad Sci U S A.12/13/2016G 431: Dairy Consumption and Body Mass Index (BMI): Mendelian Randomization and Gene-diet Interaction Analyses in CHARGEAlexis C. Frazier-WoodBMJ3/16/2017G 200: Genetic Associations with Lipoprotein Subfraction Measures Differ by Ethnicity in the Multi-Ethnic Study of AtherosclerosisAlexis C. Frazier-WoodHum Genet.3/28/2017G 284: Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.Ani ManichaikulJ Med Genet.7/1/2016G 320: Incidence of Age-Related Macular Degeneration in a Multi-Ethnic United States Population: The Multi-Ethnic Study of Atherosclerosis.Diana E. FisherOphthalmology.6/1/20165
6. MESA Genetics Published Papers: RecentTitleMESA LeadJournalPub DateG 393: A DNA methylation biomarker of alcohol consumption.Lindsay M ReynoldsMol Psychiatry11/15/2016G 415: Epigenetic Signatures of Cigarette Smoking.Roby JoehanesCirc Cardiovasc Genet.10/1/2016G 427: Secondhand Tobacco Smoke Exposure Associations with DNA Methylation of the Aryl Hydrocarbon Receptor Repressor.Lindsay M ReynoldsNicotine Tob Res.8/31/2016G 243: KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension.Ani ManichaikulHypertension.8/1/2016G 192: Genome-wide analysis identifies 12 loci influencing human reproductive behavior.Leslie RaffelNat Genet.12/1/2016G 450: Genome-wide association study of generalized anxiety symptoms in the Hispanic Community Health Study/Study of Latinos.Xiuqing Guo Am J Med Genet B Neuropsychiatr Genet.5/9/20166
7. MESA Genetics Published Papers: RecentTitleMESA LeadJournalPub DateG 409: Meta-analysis of exome chip data in relation to electrocardiographic RR intervals in European and African ancestry individuals, with the CHARGE-EX EKG consortium: The Multi-Ethnic Study of AtherosclerosisHenry J. LinHuman Molecular Genetics, HMG-2017-TF-00044.R13/18/2017G 256: Long-term outdoor air pollution and DNA methylation in circulating monocytes: results from the Multi-Ethnic Study of Atherosclerosis (MESA).Gloria C ChiEnviron Health.12/1/2016G 395: Genetic Risk Prediction of Atrial Fibrillation.Henry J. LinCirculation.4/4/20177
8. MESA Return of Results:To Confirm and Return actionable Incidental Findings to Qualified MESA Participants8
9. MESA Return of Results Project StatussourceCompletedIRB ApprovalsProtocolUCLA – submitted 3/29MOP Northwestern – submitted, awaiting approvalSpecific questionnairesWake Forest – will submit pending approval of TOPMed IRB submissionScripts (field centers/counselors)Johns Hopkins – IRB approvedVariant annotationSecured testing in CLIA labFailed contact letterInitial Decline letterResults letter9
10. MESA Epigenomic and Transcriptomic Studies (PI: Y. Liu)Data generated for MESA Exam 5 samples:DNA methylomic and transcriptomic profiling of 1,564 monocytes & 600 T cell samples using Illumina microarray chipsmiRNA-seq on a subset of 873 monocyte samplesmRNA-seq on a subset of 373 monocyte samples Plans for Exam 6 samples: DNA methylomic and transcriptomic profiling of 1,500 monocytes using sequencing technologymiRNA-seq of 400 monoctye samples Total RNA-seq of 400 monocyte samples10
11. Multi-omics in MESASteve Rich (TOPMed WGS)Mei Liu (Epigenomics)David Herrington (Metabolomics of CAD Loci)Jerry Rotter (TOPMed Multi-omics Pilot)Kent Taylor (Multi-omics Analytic Approaches)An Update11