The overall purpose of Dr. O'Donnell's research during FY 2010 has been to investigate the epidemiology and genetic epidemiology of subclinical and clinically apparent atherosclerotic cardiovascular disease and its risk factors. The longer term goal is to apply these results to prediction, prevention and personalization of cardiovascular disease medicine. The major projects have emanated from the SNP Health Association Resource (SHARe), the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium, and several DNA and RNA sequencing projects. Dr. O'Donnell is the Scientific Director and Steering Committee Chair of the NHLBI's Framingham Heart Study (FHS) SHARe Program, co-founder and Steering Committee Co-chair of the CHARGE Consortium, and Co-Director of the HeartGO Consortium of the Exome Sequencing Project. Research Subjects: The research subjects consist primarily of participants of the Framingham Heart Study FHS original cohort, Offspring cohort and Generation 3, and secondarily of participants of several collaborating cohort studies. Phenotyping: Phenotyping consisted of: (a) risk factor measures from usual clinical exams (lipids, blood pressure, anthropometric and physical examination);(b) biomarkers from peripheral blood (eg, C-reactive protein, fibrinogen, von Willebrand factor, platelet aggregation, circulating bilirubin);(c) imaging measures of subclinical atherosclerosis (coronary and abdominal and thoracic aortic atherosclerosis by multidetector CT imaging (MDCT) in 3500 Offspring and Generation 3 subjects;carotid intimal medial thickness (CIMT) and carotid plaque by B-mode ultrasonography in 3800 Offspring: thoracic and abdominal aortic plaque, LV mass and LV structure by cardiovascular magnetic resonance imaging (CMRI) in 1800);(d) clinical cardiovascular outcomes (MI, myocardial infarction;CHD, coronary heart disease;CVD, cardiovascular disease) adjudicated by a physician endpoint validation committee;(e) gene expression of lymphocyte- and platelet-derived RNA using rtPCR and whole genome RNA profiling (Affymetrix Exon Array). Genotyping in SHARe and resequencing: Genotyping derived from two dense genomewide SNP scans, a 100K SNP scan (Affymetrix platform) in 1400 FHS Offspring and original cohort subjects and a 550K SNP scan (Affymetrix platform, 250K Nsp and 250K Sty and 50K gene-focussed MIP) in 9,400 FHS subjects from all three generations. Imputation of the 550K SNPs was conducted to 2.4 million HapMap SNPs using MACH. Additionally, Next-Generation targeted and whole exome sequencing is being conducted in several US genome centers. Statistical association and linkage methods: Statistical association analyses of genotypes with phenotypes were conducted using mixed linear and/or logistic regression, generalized estimating equations, and survival analyses, when appropriate;additionally, family based association testing. Statistical linkage analyses were also conducted using SOLAR. Replication Collaboration with the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium: To seek strong evidence for replication, we combined data within a consortium of prospective, observational cohort studies with genomewide SNP scans and a large, common set of phenotypes. The core cohorts include the Iceland Age, Gene/Environment Susceptibility Study, the Cardiovascular Health Study, the Rotterdam Study and the Atherosclerosis Risk in Community Study;multiple additional cohorts are collaborating from the US and Europe. In silico replication meta-analysis is performed using a common set of 2.4 million SNPs imputed to HapMap. New Projects Underway: These new projects include (a) profiling of metabolites in collaboration with the SABRe project and separately with MGH PIs;(b) gene expression profiling and targeted gene expression in Offspring subjects;(c) pilot study of RNA sequencing through the NHLBI DNA Sequencing Core lab. Research Accomplishments for Major Projects Directed by Dr. O'Donnell in FY 2010: 1. Genetic determinants of subclinical atherosclerosis: We have completed further GWAS analysis of coronary artery calcification and abdominal aortic calcification, aortic diameters, and aortic valve calcium by MDCT;and carotid intimal medial thickness by carotid ultrasonography. Multiple genomewide significant associations have been noted. Replication meta-analyses have been completed in the CHARGE Consortium and several manuscripts submitted or in preparation. In addition, Dr. O'Donnell is a collaborating investigator in published GWAS analyses of incident heart failure (1) and heart failure mortality and major CHD risk factor phenotypes;global analysis of serum lipid levels (reported 95 loci) (2);and cigarette smoking (3). 2. Genetic determinants of ECG phenotypes: Our group contributed to published GWAS meta-analyses in the CHARGE Consortium that reported multiple loci underlying variation in heart rate (4) and QRS interval length. 3. Sequencing projects: We completed analysis of sequencing of the chromosome 9p21 region: During FY10, follow-up genotyping was performed to follow-up resequencing completed in 282 FHS subjects in a 200,000 bp in the region of chromosome 9p21 implicated in MI as well as two nearby genes, CDKN2A and CDKN2B. A manuscript is in preparation to describe phenotype-genotype associations of these variants in 7000 FHS subjects. Additionally, we contributed to a manuscript that identified sequence variants in loci implicated by GWAS underlying hypertriglyceridemia (5). 4. Genetic determinants of myocardial infarction/coronary heart disease: GWAS analysis has recently been conducted for incident and prevalent MI in FHS;replication analyses are completed in the CHARGE Consortium and MORGAM Cohort and four other cohorts;and a manuscript is in preparation to describe the replication of top SNPs. 5. Genetic determinants of hemostatic factors, platelet aggregability and biomarkers: A GWAS meta-analysis in the CHARGE Consortium was published for circulating levels of factor VII and von Willebrand factor (6), as well as platelet aggregability to epinephrine and ADP (7). Several genomewide significant associations were noted. Further research is underway for expression of genes implicated in GWAS for hemostatic and platelet traits, and an initial manuscript was published recently (8). A GWAS of erythrocyte measures reported over 25 genes associated with anemia and erythrocyte traits (9). 6. Bioinformatics Tools: Our DIR bioinformatics fellow Dr. Johnson has overseen the updating of an annotated database of all published GWAS associations. He reported the prevalence and implications of 'reportable'SNPs on GWAS SNP arrays (10). 7. Epidemiology of CHD risk and coronary artery calcium: We are developing an updated Framingham CHD risk score that includes CRP and family history of CHD in the model. Additional projects are underway to examine the association of genetic risk scores consisting of SNPs for MI identified by GWAS and SNPs for lipid levels identified by GWAS. Manuscripts for these analyses are in preparation. Selected references (out of 38 publications in PubMed and 9 publications in press from October 2009 through September 15 2010): 1. Smith NL et al. Circ Cardiovasc Genet 2010;3(3):256-66. 2. Teslovich TM et al. Nature 2010;466(7307):707-13. 3. Tobacco and Genetics Consortium. Nat Genet;42(5):441-7. 4. Eijgelsheim M et al. Hum Mol Genet 2010 Epub ahead of print. 5. Johansen CT et al. Nat Genet 2010;42(8):684-7. 6. Smith NL et al. Circulation 2010;121(12):1382-92. 7. Freedman JE et al. Circulation 2010;122(2):119-29. 8. Johnson AD et al. Nat Genet 2010;42(7):608-13. 9. Ganesh SK et al. Nat Genet 2009;41(11):1191-8. 10.Johnson AD et al. Genet Med 2010;12(6):355-63.

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Huffman, Jennifer E; de Vries, Paul S; Morrison, Alanna C et al. (2015) Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. Blood 126:e19-29
Amendola, Laura M; Dorschner, Michael O; Robertson, Peggy D et al. (2015) Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res 25:305-15
Huan, Tianxiao; Rong, Jian; Liu, Chunyu et al. (2015) Genome-wide identification of microRNA expression quantitative trait loci. Nat Commun 6:6601
Laugsand, Lars E; Ix, Joachim H; Bartz, Traci M et al. (2015) Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies. Atherosclerosis 243:44-52
Roberts, Angharad M; Ware, James S; Herman, Daniel S et al. (2015) Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 7:270ra6
Yeon, Susan B; Salton, Carol J; Gona, Philimon et al. (2015) Impact of age, sex, and indexation method on MR left ventricular reference values in the Framingham Heart Study offspring cohort. J Magn Reson Imaging 41:1038-45
Pursnani, Amit; Massaro, Joseph M; D'Agostino Sr, Ralph B et al. (2015) Guideline-Based Statin Eligibility, Coronary Artery Calcification, and Cardiovascular Events. JAMA 314:134-41
Huan, Tianxiao; Meng, Qingying; Saleh, Mohamed A et al. (2015) Integrative network analysis reveals molecular mechanisms of blood pressure regulation. Mol Syst Biol 11:799
Wessel, Jennifer; Chu, Audrey Y; Willems, Sara M et al. (2015) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun 6:5897
Nelson, Christopher P; Hamby, Stephen E; Saleheen, Danish et al. (2015) Genetically determined height and coronary artery disease. N Engl J Med 372:1608-18

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