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. 2009 Dec 15;3 Suppl 7(Suppl 7):S4.
doi: 10.1186/1753-6561-3-s7-s4.

The Genetic Analysis Workshop 16 Problem 3: simulation of heritable longitudinal cardiovascular phenotypes based on actual genome-wide single-nucleotide polymorphisms in the Framingham Heart Study

Aldi T Kraja  1 , Robert Culverhouse, E Warwick Daw, Jun Wu, Andrew Van Brunt, Michael A Province, Ingrid B Borecki
Affiliations

The Genetic Analysis Workshop 16 Problem 3: simulation of heritable longitudinal cardiovascular phenotypes based on actual genome-wide single-nucleotide polymorphisms in the Framingham Heart Study

Aldi T Kraja et al. BMC Proc. .

Abstract

The Genetic Analysis Workshop (GAW) 16 Problem 3 comprises simulated phenotypes emulating the lipid domain and its contribution to cardiovascular disease risk. For each replication there were 6,476 subjects in families from the Framingham Heart Study (FHS), with their actual genotypes for Affymetrix 550 k single-nucleotide polymorphisms (SNPs) and simulated phenotypes. Phenotypes are simulated at three visits, 10 years apart. There are up to 6 "major" genes influencing variation in high- and low-density lipoprotein cholesterol (HDL, LDL), and triglycerides (TG), and 1,000 "polygenes" simulated for each trait. Some polygenes have pleiotropic effects. The locus-specific heritabilities of the major genes range from 0.1 to 1.0%, under additive, dominant, or overdominant modes of inheritance. The locus-specific effects of the polygenes ranged from 0.002 to 0.15%, with effect sizes selected from negative exponential distributions. All polygenes act independently and have additive effects. Individuals in the LDL upper tail were designated medicated. Subjects medicated increased across visits at 2%, 5%, and 15%. Coronary artery calcification (CAC) was simulated using age, lipid levels, and CAC-specific polymorphisms. The risk of myocardial infarction before each visit was determined by CAC and its interactions with smoking and two genetic loci. Smoking was simulated to be commensurate with rates reported by the Centers for Disease Control. Two hundred replications were simulated.

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Figures

Figure 1
Figure 1
The Genetic Analysis Workshop 16 Problem 3 diagram. Figure 1 shows simulated phenotypes emulating the lipid domain (HDL, LDL, TG, and CHOL) and its contribution to cardiovascular disease risk (CAC and MI). Simulated major genes are symbolized with Greek letters. There are 1,000 polygenes for each trait HDL, LDL, and TG, several of them with pleiotropic effects. Continued lines and arrows show causality/interaction (I); dashed lines show pharmacogenetic effects only for subjects treated with medication, where response was dependent on the subjects' genotypes. Environmental factors such as diet, smoking, and medication were modeled in the simulation.
See this image and copyright information in PMC

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