Mapping metabolic traits in the diversity outbred mouse population (818.12)

Abstract

Hyperlipidemia, a risk factor for cardiovascular disease, is a complex trait regulated by a variety of dietary and genetic risk factors. Inbred mice, which exhibit strain‐specific variation in circulating lipoprotein levels, have effectively been used to model the genetic complexity of hyperlipidemia. Traditional quantitative trait locus (QTL) mapping studies using inbred strains often identify large genomic regions, containing many genes, due to limited recombination. This hampers candidate gene identification and translation of results into possible therapeutic targets. An alternative approach is the use of outbred strains for genetic mapping, such as the Diversity Outbred (DO) mouse panel recently developed by the Jackson Laboratory.Our current studies use the DO mice to map QTL for plasma lipid levels. DO mice were genotyped for 77,800 SNPs using the MegaMUGA array and founder haplotype states were predicted using a hidden Markov model. QTL mapping was carried out in R using a genetic model that incorporates reconstructed haplotypes and accounts for population structure. Our initial studies used 316 male and female DO mice fed a synthetic diet to map total cholesterol (TC) and triglyceride (TG) levels and identified a significant peak on Chromosome 1 (max LOD 8.02) and a suggestive peak on Chromosome 6 (max LOD 6.43) associated with TC. The Chromosome 1 QTL maps 1 Mb away from a well characterized gene regulating cholesterol (ApoA2). We identified two suggestive peaks on Chromosome 17 associated with TG. We have also measured plasma lipid levels and traits modeling atherosclerosis in an additional cohort of 300 female DO mice fed either a hyperlipidemia‐inducing diet or a control diet; mapping results are pending. Our studies are intended to demonstrate the value of the DO population to improve mapping resolution and aid in the identification of potential therapeutic targets for metabolic diseases.Grant Funding Source: Pilot funds from the Nutrition Obesity Research Center (P30DK056350) and the NHLBI (4R00HL102223)