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.

Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36

“…a SNP effects on heart CD36 expression (ILMN_1784863; Illumina HumanHT-12 v4) from a genome wide eQTL dataset in nondiseased tissue of 129 Western Europeans (45). Supplemental Material can be found at: (52).…”

Genome-Wide Polyadenylation Maps Reveal Dynamic mRNA 3′-End Formation in the Failing Human Heart

“…A main finding is the robust decrease of PABPN1 protein because this gene has been identified as a suppressor of APA. 5 This suggests that the observed loss of PABPN1 in heart failure may have contributed to 3′UTR shortening of at least some candidates. Gene-targeting studies that directly examine the role of PABPN1 in the mouse heart would be important to further delineate its role in heart failure.…”

“…To reliably monitor genome-wide APA events, we developed an enhanced 3′-Seq protocol (e3′-seq) that improves 3′-mRNA cleavage site (CS) position mapping and quantification 5 (Methods section in the Online Data Supplement). A flow chart of the e3′-Seq procedure and an example of 3′read mapping and CS identification is shown in Figures 1A and 1B and Online Figure I.…”

“…Control heart samples were drawn from a set of non-diseased donor heart samples previously used for eQTL analysis. 5 Barcoded cDNA fragments of poly(A)+ RNA were subsequently sequenced on a HiSeq 2000 instrument from Illumina with 2 × 100 bp PE chemistry. Gene level quantification was performed using htseq-count and genome assembly GCRh37.…”

Genetics of Sudden Cardiac Death

“…This will become increasingly possible because the expression quantitative trait loci resources in human heart continue to expand. 186,187 Furthermore, the rapid developments in functional annotation of noncoding regulatory elements of the genome (eg, enhancers 188 and noncoding RNAs 189 ) and in related technologies (eg, ChIP-seq, chromosome conformation capture) will continue to increase our ability to understand the genetic mechanisms operative at these loci. 190 An example of how such integrative approaches could facilitate this comes from the recent collaborative work of many groups on the genetic mechanism of rs6801957 located intronically in SCN10A.…”