Abstract
Cholesterol is a lipid that is essential in membrane structure and function and that is a precursor
for bile acid and steroid hormone synthesis. In humans, elevated plasma cholesterol levels are
an important cardiovascular risk factor, as they predispose to the development of
atherosclerosis. Understanding cholesterol metabolism is therefore the focus of extensive
research. Yet, if there is evidence for substantial genetic contributions to variations in
cholesterol levels, the underlying functional genetic architecture remains largely unknown and
current approaches have yielded results of little predictive value regarding future disease
occurrence. It is now becoming commonly accepted that complex traits, like plasma cholesterol
levels, are the product of complex molecular networks, modulated by sets of genetic loci and
environmental factors. To address these complexities, it is necessary to study cholesterol
metabolism as a whole system and to get an understanding of the interacting effects of its
individual parts. Here, we propose a systems genetics approach of the cholesterol biosynthetic
pathway in genetically diverse BXD-type recombinant mouse lines. For this, we have combined
large-scale genomic, transcriptomic and phenomic results and integrated it to reconstruct the
co-expression network of cholesterol biosynthetic genes. We identified a set of new genes,
previously not known to be involved in cholesterol metabolism. In particular, Echdc1 is one of
the promising candidates and it was shown that variations in its sequence and transcript
abundance are significantly associated to plasma cholesterol levels. We believe that examining
the role of these genes will provide new insights on the regulation of cholesterol biosynthesis
and on the basis of cholesterol level variability among individuals in a genetically admixed
population. Translation to humans may eventually have clinical implications in prediction of
disease risk and response to treatment and drug development.