Most genetic variants associated with complex traits occur in non-coding genomic regions and are hypothesized to affect gene expression. To identify variants that regulate gene expression, we performed cis- and trans-expression quantitative trait locus (cis/trans-eQTL) analyses using whole blood RNA-seq and whole genome sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program from 6,602 samples of predominantly European (68%), African (21%) and Indigenous American (10%) ancestry. We hypothesized that many trans signals would overlap cis signals, enabling identification of candidate genes mediating trans effects.
At a MAF ≥ 0.01, we identified 19,422 genes with ≥ 1 cis-eQTL (5% FDR; cis-eGenes) and 71,092 total independent cis-eQTLs (SuSiE 95% credible sets). At MAF ≥ 0.05, we identified 1,743 trans-eGenes. Trans-eVariants were enriched for overlap with cis-eQTL credible sets (Fisher’s exact test against MAF-matched variants; odds ratio = 8.4; p = 3x10-45; 30% of unique trans-eVariants overlap cis-eQTL) and cis-eGenes for cis-eQTL overlapping trans-eQTL were 3.5-fold enriched for transcription factor genes (p < 5e-4). 167 variants were trans-eQTL for >1 gene (1,075 total genes). For example, one cis-eVariant for ERN1, which encodes endonuclease IRE1a, was a trans-eVariant or in high LD (>0.9) with a trans-eVariant for thirteen trans-eGenes, including known ERN1 downstream target XBP1 and XBP1 target genes including DNAJB9. ERN1 is a regulator of the endoplasmic reticulum (ER) stress response, and five of the twelve trans-eGenes in the KEGG database were in the “Protein processing in ER” pathway (31.6-fold enrichment; nominal p=1.8x10-7). Among ER response pathways IRE1a-XBP1 is the most highly conserved, with an emerging role in regulation of inflammation and immune response.
To identify trans-eGenes that may share multiple signals with a potentially regulatory cis- eGene, we finemapped trans-eQTL signals within the 2Mb window centered on each trans-eGene’s lead trans-eVariant. Within the 2Mb windows, 300 of the 1,743 trans-eGenes had >1 trans-eQTL (2,080 total trans-eQTL credible sets). We found 31 cis-eGenes with > 1 cis-eQTL signal colocalizing with > 1 trans-eQTL signal from at least one trans-eGene (145 unique cis-eGene - trans-eGene pairs). For example, trans-eGene BTN3A3 showed 4 trans-eQTL credible sets that colocalized with 4 cis-eQTL credible sets for its known regulator NLRC5. This example provides proof-of-principle for our hypothesis.
In summary, this dataset demonstrates the utility of large eQTL studies to provide insight into regulatory pathways involving trans-eQTLs mediated by cis-eGenes.