The primary goal of this renewal application from the NHLBI Family Heart Study (FHS) investigators is to identify the genomic regions linked and/or associated with CHD, atherosclerotic burden measured by ultrasound, and their risk factors. A secondary aim is to characterize interactions and the genetic epidemiology of CHD risk factors in terms of the identified genomic regions. The recently completed genome-wide scan, conducted upon large FHS samples of extended pedigrees, will allow detection of genes in the range of 10-15 percent (locus-specific) heritability.
A third aim i s to do a limited, focused amount of denser genotyping of markers in the most promising regions, to verify the results and begin to more precisely define the peaks. State of the art analytic methods and software will be applied, drawing on the complementary genetic epidemiology expertise assembled at five sites of the FHS, with scientific, analytic, and data management support from the FHS Coordinating Center. The plans are sharply focused on completing the analysis and publication of the genome scans. Novel genetic analysis methods will be used to address the issues of phenotypic, genetic and population heterogeneity, epistasis, complex interactions among the genetic and environmental risk factors, and to optimize the detection of genomic regions affecting CHD susceptibility and the risk factors. The notorious issue of multiple comparisons in genome scans will be bypassed altogether with the use of novel global testing procedures. During a previous funding cycle of the FHS, we extensively characterized the CHD and associated traits in subjects from 583 random sample pedigrees, 649 coronary heart disease (CHD)-prone pedigrees, and 59 African-American pedigrees (5,818 individuals) drawn from four epidenuologically defined populations, with banking of high quality DNA. Analysis and publication of these phenotypic data was actively pursued while genotyping was underway for selected candidate genes as well as for a coarse map of 244 Utah markers on 1,184 high risk siblings. Although not originally anticipated, an additional dense map of 404 markers is now available from the Mammalian Genotyping Service on 3,027 individuals from the 401 largest extended FHS pedigrees. Current funding expired in July 2000, too late to analyze this unanticipated genotyping that has now been completed on the majority of the largest and most informative FHS pedigrees. This extension will make this unique resource available for identifying genomic regions influencing a wide variety of CHD associated traits from all major risk factor domains.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL056567-05A1S1
Application #
6495228
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Sholinsky, Phyliss
Project Start
1996-08-15
Project End
2004-08-31
Budget Start
2001-09-05
Budget End
2002-08-31
Support Year
5
Fiscal Year
2001
Total Cost
$88,944
Indirect Cost
Name
Washington University
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Laramie, Jason M; Wilk, Jemma B; Williamson, Sally L et al. (2009) Multiple genes influence BMI on chromosome 7q31-34: the NHLBI Family Heart Study. Obesity (Silver Spring) 17:2182-9
Feitosa, Mary F; North, Kari E; Myers, Richard H et al. (2009) Evidence for three novel QTLs for adiposity on chromosome 2 with epistatic interactions: the NHLBI Family Heart Study. Obesity (Silver Spring) 17:2190-5
Yu, Kai; Zhang, Shuanglin; Borecki, Ingrid et al. (2005) A haplotype similarity based transmission/disequilibrium test under founder heterogeneity. Ann Hum Genet 69:455-67
Yu, Kai; Gu, C Charles; Xiong, Chengjie et al. (2005) Global transmission/disequilibrium tests based on haplotype sharing in multiple candidate genes. Genet Epidemiol 29:323-35
Hsu, Fang-Chi; Zaccaro, Daniel J; Lange, Leslie A et al. (2005) The impact of pedigree structure on heritability estimates for pulse pressure in three studies. Hum Hered 60:63-72
Yu, Kai; Xu, Jun; Rao, D C et al. (2005) Using tree-based recursive partitioning methods to group haplotypes for increased power in association studies. Ann Hum Genet 69:577-89
Yu, K; Gu, C Charles; Province, M et al. (2004) Genetic association mapping under founder heterogeneity via weighted haplotype similarity analysis in candidate genes. Genet Epidemiol 27:182-91
Corbett, Jonathan; Gu, C Charles; Rice, John P et al. (2004) Power loss for linkage analysis due to the dichotomization of trichotomous phenotypes. Hum Hered 57:21-7
Djousse, Luc; Pankow, James S; Arnett, Donna K et al. (2004) Apolipoprotein E polymorphism modifies the alcohol-HDL association observed in the National Heart, Lung, and Blood Institute Family Heart Study. Am J Clin Nutr 80:1639-44
Province, Michael A (2002) Searching for the mountains of the moon: genome scans for atherosclerosis. Curr Atheroscler Rep 4:169-75

Showing the most recent 10 out of 14 publications