Abstract 204: Prioritizing Genome-Wide Association Study Lipid Loci With Global Gene Networks

Abstract

Large genome-wide association studies (GWAS) conducted in humans by the Global Lipids Genetics Consortium (GLGC) have identified more than 150 genome-wide significant loci that are associated with variation in plasma lipid levels (cholesterol, LDL/HDL-cholesterol, and triglycerides). Some loci contain genes with well-described roles in lipid metabolism, such as CETP , LDLR , and APOB ; however, for many genome-wide significant loci, there is no clear causal gene. To test the hypothesis that lipid genes in the liver are co-regulated, we constructed global co-expression gene networks from genome-wide gene expression data obtained from the livers of multiple independent mouse genetic crosses. All together, we constructed global gene networks from eight distinct studies, representing more than 800 unique mice of diverse genetic backgrounds. For all studies analyzed, we identified a module (or sub-network) of genes that is significantly enriched (p<1x10 -15 ) functionally for cholesterol biosynthesis and metabolism genes. This module ranges in size from 70 to 824 genes across the eight studies and contains all genes involved in the cholesterol biosynthesis pathway ( Acat2, Hmgcs2, Hmgcr, Lss, Sc5d, etc. ). This module also contains many genes involved in the regulation of cholesterol metabolism, such as Ldlr , Pcsk9 , and Insig1 . Because of the significant enrichment of cholesterol genes in this module, we have begun to cross-reference all genes in the module against the GLGC lipid GWAS data. Through this analysis, we have identified genes of unknown function that are clearly located within genome-wide significant lipid loci as well as sub-threshold (suggestive significant) lipid loci. Among the genes we identified was Sestrin1 , which was located within a clear sub-threshold locus associated with plasma cholesterol (rs12206606; p=1.4 x 10 -5 ). In conclusion, our studies provide a framework to identify causal genes within reported lipid GWAS loci as well as to identify novel sub-threshold loci associated with variations in lipids among humans. We illustrate the approach by identifying Sestrin1 within a sub-threshold locus associated with plasma cholesterol levels and show that Sestrin1 is transcriptionally regulated in the liver by dietary cholesterol.