There are several components of the research program. Component 1: Platelet Biology, Reactivity and Genomics. Utilizing one of the largest human samples (FHS: Framingham Heart Study) with platelet reactivity we have conducted deeper genetic scans for contributing genes. These scans use new genetic maps with deeper coverage of rare variation. DNA genotyping of an additional diverse population sample, the FHS OMNI cohort, was supported allowing additional validation samples and gene coverage for platelet reactivity traits. Targeted qPCR RNA measurements in FHS platelet samples are also completed and underway to investigate mechanistic questions for specific candidate genes. Separately, platelet RNA samples were collected from 32 myocardial infarction samples and whole transcriptome RNA sequencing supported to identify genes associated with different factors and diagnoses. Additional cell line and anonymous tissue samples were purchased to augment this work with future RNA sequencing. Component 2: Tissue-specific Gene Expression. A major cell- and tissue-specific database of genetic factors on gene expression (eQTLs) was maintained and updated. This catalog was used to add information on genes to many disease and risk factor studies, primarily in the cardiovascular and metabolic disease domains. In a separate project, gene expression measurements in whole blood samples from >5,300 FHS samples were employed in studies to identify genes whose RNA levels correlated with traits, including new eQTLs. A major study was undertaken to integrate FHS gene expression data with data on 15,000 other samples, leading to the identification and validation of >1,200 genes whose RNA levels change during aging. Research was supported to conduct experiments knocking out some of these novel genes in the worm C. elegans in order to assess whether they significantly affect lifespan. Component 3: Development and Application of Bioinformatics Resources. Beyond the eQTL database mentioned above, a large genome-wide association study (GWAS) results database was updated, and an online NIH query site developed. This database of results from 1,400 GWAS articles was used in research addressing multiple questions including the convergence of GWAS genetic evidence shared in common for cancer and cardiometabolic diseases;convergence of GWAS disease traits on drug targeted genes, suggesting possible novel drug targets or therapeutic re-positionings;and a study on convergence of GWAS findings with tissue-specific eQTL findings. Ongoing updating of the database was supported.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2013
Total Cost
$270,130
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Sen, Shurjo K; Boelte, Kimberly C; Barb, Jennifer J et al. (2014) Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification. Am J Hum Genet 95:66-76
Zhang, Xiaoling; Gierman, Hinco J; Levy, Daniel et al. (2014) Synthesis of 53 tissue and cell line expression QTL datasets reveals master eQTLs. BMC Genomics 15:532
Keller, Margaux F; Reiner, Alexander P; Okada, Yukinori et al. (2014) Trans-ethnic meta-analysis of white blood cell phenotypes. Hum Mol Genet 23:6944-60
Simino, Jeannette; Shi, Gang; Bis, Joshua C et al. (2014) Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. Am J Hum Genet 95:24-38
Ganesh, Santhi K; Chasman, Daniel I; Larson, Martin G et al. (2014) Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. Am J Hum Genet 95:49-65
Yao, Chen; Joehanes, Roby; Johnson, Andrew D et al. (2014) Sex- and age-interacting eQTLs in human complex diseases. Hum Mol Genet 23:1947-56
Zhang, Xiaoling; Johnson, Andrew D; Hendricks, Audrey E et al. (2014) Genetic associations with expression for genes implicated in GWAS studies for atherosclerotic cardiovascular disease and blood phenotypes. Hum Mol Genet 23:782-95
Narayanan, Manikandan; Huynh, Jimmy L; Wang, Kai et al. (2014) Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases. Mol Syst Biol 10:743
Cornes, Belinda K; Brody, Jennifer A; Nikpoor, Naghmeh et al. (2014) Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. Circ Cardiovasc Genet 7:374-82
Escott-Price, Valentina; Bellenguez, CĂ©line; Wang, Li-San et al. (2014) Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. PLoS One 9:e94661

Showing the most recent 10 out of 22 publications