Dynamic role of trans-regulation of gene expression in relation to Complex traits

In genome-wide association studies (GWAS), identifying causal DNA-sequence genetic variants and understanding their mechanisms of effect on the trait being studied remains a challenge. In particular, how these genetic variants, [e.g. expression quantitative trait loci distant from the gene they control (trans-eQTLs)] affect expression of remote genes (trans-eGenes) remains unknown. Authors [see attached article] hypothesized that some trans-eQTLs regulate expression of distant genes by altering the expression of nearby genes (cis-eGenes). [By “nearby”, “cis” refers to distances of perhaps 20 or 100 kilobases maximum.]

Using published GWAS data sets with 39,165 single-nucleotide variants (SNVs) associated with 1,960 traits, authors explored whole-blood

gene expression associations of trait-associated SNVs in 5,257 individuals from the Framingham Heart Study. They identified 2,350 trans-eQTLs (at P <10–7); more than 80% of them were found to have cis-associated eGenes. Mediation testing suggested that, for 35% of trans-eQTL/trans-eGene pairs in different chromosomes, and 90% pairs in the same chromosome, the disease-associated SNV may alter expression of the trans-eGene via cis-eGene expression. Using causal inference testing, authors searched causal variants across eight cardiometabolic traits and identified several cis-eGenes (ALDH2 for systolic and diastolic blood pressure, MCM6 and DARS for total cholesterol, and TRIB1 for triglycerides) that were causal mediators for the corresponding traits –– as well as examples of trans-mediators (TAGAP for LDL cholesterol). The finding of extensive evidence of genome-wide mediation effects suggests a critical role of cryptic gene regulation underlying many disease traits. DwN Am J Hum Genet April 2o17; 100: 571–580

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