Combining genome-wide data from humans and animal models of dyslipidemia and atherosclerosis

Abstract

Purpose of review: Comparative genomics allows researchers to combine genome-wide association data from humans with studies in animal models in order to assist in the identification of the genes and the genetic variants that modify susceptibility to dyslipidemia and atherosclerosis.

Recent findings: Association and linkage studies in human and rodent species have been successful in identifying genetic loci associated with complex traits, but have been less robust in identifying and validating the responsible gene and/or genetic variants. Recent technological advancements have assisted in the development of comparative genomic approaches, which rely on the combination of human and rodent datasets and bioinformatics tools, followed by the narrowing of concordant loci and improved identification of candidate genes and genetic variants. Additionally, candidate genes and genetic variants identified by these methods have been further validated and functionally investigated in animal models, a process that is not feasible in humans.

Summary: Comparative genomic approaches have led to the identification and validation of several new genes, including a few not previously implicated, as modifiers of plasma lipid levels and atherosclerosis, yielding new insights into the biological mechanisms of these complex traits.

Figure 1

Use of bioinformatic tools including comparative genomics to refine a QTL interval. Hypothetical example of a mouse complex trait QTL with the shaded regions representing the QTL region of interest through stepwise analyses as denoted. The respective size (in megabases) and number of genes are shown on the right. Black lines within each of the individual and combined mouse QTLs represent the QTL peaks. Adapted from Burgess-Herbert SL, et al. [10]

Figure 2

Diagram of various strategies to combine animal and human studies to help identify candidate genes and regulatory regions for complex traits. Although we refer to mouse studies, these strategies may be applied to other species as well.