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.
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