Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies

Abstract

Background: Identification of single nucleotide polymorphisms (SNPs) associated with gene expression levels, known as expression quantitative trait loci (eQTLs), may improve understanding of the functional role of phenotype-associated SNPs in genome-wide association studies (GWAS). The small sample sizes of some previous eQTL studies have limited their statistical power. We conducted an eQTL investigation of microarray-based gene and exon expression levels in whole blood in a cohort of 5257 individuals, exceeding the single cohort size of previous studies by more than a factor of 2.

Results: We detected over 19,000 independent lead cis-eQTLs and over 6000 independent lead trans-eQTLs, targeting over 10,000 gene targets (eGenes), with a false discovery rate (FDR) < 5%. Of previously published significant GWAS SNPs, 48% are identified to be significant eQTLs in our study. Some trans-eQTLs point toward novel mechanistic explanations for the association of the SNP with the GWAS-related phenotype. We also identify 59 distinct blocks or clusters of trans-eQTLs, each targeting the expression of sets of six to 229 distinct trans-eGenes. Ten of these sets of target genes are significantly enriched for microRNA targets (FDR < 5%). Many of these clusters are associated in GWAS with multiple phenotypes.

Conclusions: These findings provide insights into the molecular regulatory patterns involved in human physiology and pathophysiology. We illustrate the value of our eQTL database in the context of a recent GWAS meta-analysis of coronary artery disease and provide a list of targeted eGenes for 21 of 58 GWAS loci.

Fig. 1

Genomic eQTL location vs. transcript cluster location for highly significant eQTL-gene pairs (FDR < 1E-8). Bubble size is inversely proportional to the FDR. The largest bubble indicates FDR < 1E-100

Fig. 2

Box plots of very strong cis-eQTL or trans-eQTL-transcript cluster pairs. a rs2499412 – TMEM164 (cis, R² = 47%). b rs3773654 – PEX11A (trans, R² = 16%). y-axis: expression level in RMA units; x-axis: imputed major allele count

Fig. 3

Number of transcript clusters targeted by each trans-eQTL. eQTLs targeting six or more extrachromosomal transcript clusters fall into color-coded clusters. a Number of extra-chromosomal trans targets. b Number of intrachromosomal trans targets. Note presence of unlabeled clusters on Chr 6, the HLA region, and on Chr 8

Fig. 4

Screenshot of NCBI molecular QTL browser