Genome-wide identification of expression quantitative trait loci (eQTLs) in human heart

Abstract

In recent years genome-wide association studies (GWAS) have uncovered numerous chromosomal loci associated with various electrocardiographic traits and cardiac arrhythmia predisposition. A considerable fraction of these loci lie within inter-genic regions. The underlying trait-associated variants likely reside in regulatory regions and exert their effect by modulating gene expression. Hence, the key to unraveling the molecular mechanisms underlying these cardiac traits is to interrogate variants for association with differential transcript abundance by expression quantitative trait locus (eQTL) analysis. In this study we conducted an eQTL analysis of human heart. For a total of 129 left ventricular samples that were collected from non-diseased human donor hearts, genome-wide transcript abundance and genotyping was determined using microarrays. Each of the 18,402 transcripts and 897,683 SNP genotypes that remained after pre-processing and stringent quality control were tested for eQTL effects. We identified 771 eQTLs, regulating 429 unique transcripts. Overlaying these eQTLs with cardiac GWAS loci identified novel candidates for studies aimed at elucidating the functional and transcriptional impact of these loci. Thus, this work provides for the first time a comprehensive eQTL map of human heart: a powerful and unique resource that enables systems genetics approaches for the study of cardiac traits.

Figure 1. Overview plots for top cis eQTLs.

An overview of the 4 most significant cis eQTLs: rs11150882 with C17orf97 (panel A), rs11158569 with CHURC1 (panel B), rs2779212 with ZSWIM7 (panel C) and rs2549794 with ERAP2 (panel D). On the left of each panel, box-and-whisker plots of mRNA levels for all genotypes. On the right, mean and standard-error plots of mRNA levels for all genotypes are illustrated. Right upper corner gives the association p-value and the gene name.

Figure 2. eQTL overview plots for 4 cardiac trait GWAS candidate genes.

An overview of 4 GWAS cis eQTLs: rs9912468 with PRKCA (panel A), rs7912445 with GNB4 (panel B), rs8049607 with LITAF (panel C) and rs6882776 with NKX2-5 (panel D). On the left of each panel, box-and-whisker plots of mRNA levels for all genotypes. On the right, mean and standard-error plots of mRNA levels for all genotypes are illustrated. Right upper corner gives the association p-value and the gene name.