Abstract 18436: Systems Biology Identifies a Gene Driving Expression of Metabolic Syndrome in Lyon Rats

Abstract

The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. The Lyon Hypertensive (LH) and Lyon Normotensive (LN) rats are models of MetS sensitivity and resistance, respectively. To identify genetic loci influencing phenotypes underlying MetS, an F2 intercross between LH and LN was studied to identify physiological quantitative trait loci (pQTL) contributing to plasma lipid and leptin levels, blood pressure, and body weight/adiposity. We performed mRNA-seq in F2 rats to identify the loci regulating gene expression, or expression (e)QTL, followed by gene expression network analyses. Systems biology methods were applied to identify candidate MetS genes, including genes previously shown to be MetS-related. We found an eQTL hotspot on RNO17, which was also located within pQTLs for MetS-related traits. The genes regulated by this eQTL hotspot were mainly in two co-expression network modules (a mitochondria related module and a gene regulation related module) and causally affect many MetS-related traits. Multiple evidences strongly and consistently support RGD1562963, a gene regulated in cis by this eQTL hotspot as the eQTL driver gene directly affected by genetic variation between LH and LN rats. Our study sheds light on the intricate pathogenesis of MetS and that systems biology with high-throughput sequencing is a powerful method to study the etiology of complex multifactorial diseases.