Links to Methodology and Data:
Overview of Project 5:
We are comprehensively characterizing common genetic variation (linkage disequilibrium [LD] structure) in 52 candidate genes and identifying common missense variants in an additional 150 candidate genes identified by the mouse and human studies described in Projects 1-4, and determining which of these genotypes are associated with echocardiographic measures of left ventricular size and function among members of the
Framingham Heart Study (FHS). DNA samples from the Framingham cohort are sent to the
Broad Institute for genetic analysis.
The primary goals of Project 5 of the PGA are:
- To identify common missense single nucleotide polymorphisms (DNA sequence variants) of known and newly characterized candidate genes by using high-throughput resequencing technology.
- Characterize common genetic variation in a set of 50 highest priority candidate genes. We genotype SNPs from public and private databases as well as our own resequencing effort to create high-resolution linkage disequilibrium maps of SNPs.
- To select sets of tag SNPs (tSNPs) that efficiently capture common variation in 50 highest priority candidate genes.
- To genotype missense SNPs from (1) and tSNPs from (2) in 1811 participants of the Framingham Heart Study.
- To test the association of missense SNPs and tag SNPs with left ventricular mass, left ventricular and left atrial chamber size, aortic root size and related secondary measures (LV ejection fraction and fractional wall shortening) in a well characterized population-based cohort using a staged two-step analysis that includes both
- Population-based case-control methods
- Replication in an independent sample of related individuals using family-based association tests
Secondary goals include:
- To explore possible gene-environment
interactions with age, sex, blood pressure, body mass index and other covariates.
- To develop bioinformatics tools to detect
higher order genomic interactions that will permit whole-genome association studies.
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