Genetical Genomics Approaches to Familial Combined Hyperlipidemia
Christopher L Plaisier
Doctor of Philosophy in Human Genetics
University of California, Los Angeles, 2009
Professor Päivi Pajukanta, Chair
Genetical genomics approaches integrate genotypic, gene expression, and phenotypic information to identify genetic variants that predispose to disease. The benefit of this approach is that it provides a plausible molecular mechanism for disease associated variants through allele-dependent effects on transcript levels. Through a collaborative effort, we developed a Mexican gene expression microarray dataset of familial combined hyperlipidemia (FCHL) case/control fat biopsies that we utilized in genetical genomics approaches to identify variants predisposing to FCHL in Mexicans. To reduce confounding due to admixture in the Mexican population, a novel method that estimates ancestral proportions for individuals was developed. We then demonstrated that two genetic variants in transcription factor 7-like 2 (TCF7L2) were associated with triglycerides (TGs) and that TCF7L2 expression was associated with lipid traits in Mexican fat biopsies. In the third study, we identified a promoter variant upstream of the positional candidate gene galanin preproprotein (GAL) associated with TGs. We observed an allele-dependent effect of the GAL promoter variant on DNA binding affinities and transcriptional activation in vitro. Then we demonstrated that many lipid related genes were differentially expressed in an allele-dependent manner by the GAL promoter variant in Mexican fat biopsies. In our final study, we provided evidence that the TG- and FCHL-associated genetic variant in upstream transcription factor 1 (USF1) has an effect on global expression profiles in Mexican fat biopsies and that this effect is mediated by USF1. We applied weighted gene co-expression network analysis to the Mexican FCHL fat biopsies and identified two TG-associated co-expression modules. One of these modules was also associated with FCHL and USF1 genotypes. This same module contained 18 causal candidate genes for FCHL. A genetic variant from the causal candidate gene fatty acid desaturase 3 (FADS3) had prior evidence of association with TGs in Caucasians and we replicated this association in Mexicans. Taken together, our genetical genomics approaches implicate five new variants for FCHL and suggest a plausible mechanism for their predisposition to FCHL.