THE GENETIC ARCHITECTURE OF ATHEROSCLEROSIS AND THE ATHEROSCLEROSIS-ASSOCIATED METABOLITE TRIMETHYLAMINE-N-OXIDE IN THE DIVERSITY OUTBRED MOUSE POPULATION

Inbred mice exhibit strain-specific variation in susceptibility to complex diseases which renders them useful for dissecting the genetic architecture of these traits. Traditional quantitative trait locus (QTL) mapping studies using inbred strains often identify large genomic regions containing many genes and require extensive follow up studies to identify the causal genes underlying the associations. Alternatively, the use of recently developed multi-parent outbred mice designed to be informative for QTL mapping, such as the Diversity Outbred (DO) mouse population, can expedite the identification of causal genes and variants associated with complex diseases. Here, we used DO mice to study the genetic architecture of atherosclerosis and multiple risk factors associated with this complex disease. We fed 292 female DO mice either a high-fat, cholesterol-containing diet to induce atherosclerosis or a low-fat, high-protein control diet for 18 weeks. We then quantified multiple metabolic phenotypes before and after dietary treatment and measured aortic lesion size in the mice after dietary treatment. We performed linkage mapping for these quantitative traits using a linear regression model based on reconstructed founder haplotypes. The additive haplotype model used produces estimates of the effects of the founder alleles which can be used to inform follow up studies and to identify the causal variants underlying the QTL. Among our highly significant results, we identified QTL associated with atherosclerosis, triglycerides, cholesterol, choline, trimethylamine-N-oxide, blood urea nitrogen, and insulin resistance in this cohort of DO mice. These results demonstrate the value of the DO population to improve mapping resolution and to aid in the identification of potential therapeutic targets for complex diseases.Doctor of Philosoph