Abstract 35: Transcriptome-wide Association Study of Circulating Lipid Levels

Genome-wide association studies have identified scores of DNA variants that are associated with circulating lipid levels. We conducted a transcriptome-wide association study (TWAS) of triglycerides (TG), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and total cholesterol (TC) using whole blood derived RNA from 1,838 Framingham Heart Study participants using the Affymetrix GeneChip Human Exon 1.0 ST array. External replication was conducted in four separate population-based cohorts (SHIP-TREND, KORA F4, Rotterdam Study, InChianti) totaling 3,244 individuals assayed using the Illumina HumanHT-12 Expression BeadChip array. Individuals taking lipid-lowering medications were excluded from analysis. Models were adjusted for age, sex, blood cell counts, and technical covariates (e.g., batch). Using a stringent transcriptome-wide FDR of 0.05 in both discovery and replication results, there were 119 significant transcript associations for TG; 57 for HDL-C; 1 for LDL-C; and 3 for TC. Expression levels of HDC and CPA3 genes were the two strongest associations with all 4 lipid traits in both discovery and replication cohorts. Known lipid pathway gene MYLIP was inversely associated with triglycerides (replication P=6.4x10-45) and directly associated with HDL-C levels (replication P =3.5x10-26). ABCA1 was also directly associated with triglyceride levels (replication P =9.4x10-50). In summary, through TWAS we identified many known and novel genes whose expression levels in whole blood were associated with circulating lipid levels. We believe that TWAS may serve as a useful method for identifying novel therapeutic targets. However, further studies are needed to elucidate the role that these genes may play in regulating circulating lipid levels or mediating the effect of lipids on atherosclerotic cardiovascular diseases.