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.
Highlights
It is well established that many cardiac traits and susceptibility to heart disease are heritable [1,2,3,4,5,6,7]
Data preprocessing and normalization Gene transcript abundance: Of the 47,231 transcripts whose expression levels were measured on the array, only those that were expressed above background level and for which the probe sequence mapped unambiguously to the genome and did not contain common single nucleotide polymorphisms (SNPs), were used in further analyses
We conducted a genome-wide expression quantitative trait locus (eQTL) analysis in 129 samples of normal human myocardium, identifying genetic variation regulating gene expression in human heart and uncovering 771 genome-wide significant independent eQTLs. This resource, heretofore unavailable in human heart will contribute to advancing our understanding of the genetic mechanisms underlying loci associated with cardiac traits
Summary
It is well established that many cardiac traits and susceptibility to heart disease are heritable [1,2,3,4,5,6,7]. Several genome-wide association studies (GWAS) have uncovered common genetic variation, in the form of single nucleotide polymorphisms (SNPs), impacting on cardiac traits such as susceptibility to atrial fibrillation [8], ventricular fibrillation [9], heart rate [10] and electrocardiographic (ECG) indices of cardiac conduction [11,12,13,14] and repolarization [15,16]. Many trait-associated haplotypes occur in non-coding regions of the genome [17] and are hypothesized to modulate the respective trait through effects on gene expression [18]. Because eQTLs may be tissue-specific, a similar resource for human heart is anticipated to have great value [23,29,30,31]
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