Abstract 16053: Dynamic Trans Gene Expression Regulation by eQTLs in Complex Disease Traits
Genome-wide association studies (GWAS) have been widely used to identify genetic variants associated with complex traits. However, for many of these diseases, it remains unclear how the genetic variants exert their effect on the phenotype, and especially how they affect gene expression of remote genes (trans-eQTL). In a previous study, we found that a large proportion of trans-eQTLs are also cis-eQTLs. Therefore, we hypothesized that some trans-eQTLs influence expression of distant genes through effects on expression levels of a cis-transcript. Using 42,271 SNPs associated with 1,960 complex traits available in public data sets curated in GRASP, we first explored the gene expression associations of trait-associated SNPs in 5,257 individuals from the Framingham Heart Study (FHS) and then we tested mediation effects of cis-transcripts on trans-transcripts when both were associated with the same eQTL. At FDR<0.05, we identified 2,324 trans-eQTLs; 84% of them (1,953) were found to have cis-associated transcripts. Mediation testing suggested that for 797 (41%) of these 1953 trans-eQTLs, the disease-associated SNP may alter expression of the trans-transcript via expression of genes near the eQTL (p<0.0005 for 10,000 permutations). We searched across 7 cardiometabolic traits (BMI, systolic/ diastolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, glucose) and identified several cis mediators affecting the expression of multiple downstream genes; the cis mediators include SH2B3, ALDH2, NLRC5, PCSK7 and ALAS2. The expression of each cis mediator gene was significantly associated with one or more CVD phenotype in 5,257 FHS participants. These findings highlight a novel approach to identifying promising drug targets.
Author Disclosures: C. Yao: None. R. Joehanes: None. T. Huan: None. C. Liu: None. A.D. Johnson: None. J. Freedman: None. P.J. Munson: None. D. Levy: None.
- © 2015 by American Heart Association, Inc.