Integrative Genetic Analysis of Behavioral and Metabolic Traits in an Advanced Intercross Line of Mice

Mice are one of the primary organisms used to study mammalian behavior and physiology. The goal of this study was to identify genes in the mouse that would allow us to develop specific, testable hypotheses about the mechanisms underlying complex human traits, including psychiatric and metabolic diseases. We used a simple mouse outbred population, the LG/J x SM/J advanced intercross line (AIL; Aap:LG,SM-G50-56), to identify 126 quantitative trait loci (QTLs) for the locomotor response to methamphetamine, prepulse inhibition of the acoustic startle reflex, body weight, muscle weight, and various other behavioral and physiological traits. A key advantage of studying model organisms is the ability to procure primary tissue for functional genomic analysis. Integrating phenotype, genotype, and gene expression data collected from the same individuals can accelerate the process of gene identification and provide insight into the biological mechanisms that influence complex traits. Therefore, we used RNA-sequencing to measure gene expression QTLs (eQTLs) in the hippocampus, prefrontal cortex, and striatum of approximately 200 AIL mice that were phenotyped and genotyped. We identified over 2,000 cis-eQTLs and over 400 trans-eQTLs in each brain region and integrated these data with QTLs to identify candidate genes. Our work demonstrates that an integrative analysis of genotype, phenotype and gene expression data is a powerful approach that can accelerate the process of gene identification and provide insight into the biology of complex traits.