Genome-Wide Identification of Expression Quantitative Trait Loci (eQTLs) in Human Heart.

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

Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5

Activation of postsynaptic metabotropic glutamate receptors (mGluRs) modulates neuronal excitability and synaptic plasticity, while deregulation of mGluR signaling has been implicated in neurodevelopmental disorders. Overstimulation of mGluRs is restricted by the rapid endocytosis of receptors after activation. However, how membrane trafficking of mGluRs at synapses is controlled remains poorly defined. We find that in hippocampal neurons, the agonist-induced receptor internalization of synaptic mGluR5 is significantly reduced in Shank knockdown neurons. This is rescued by the re-expression of wild-type Shanks, but not by mutants unable to bind Homer1b/c, Dynamin2, or Cortactin. These effects are paralleled by a reduction in synapses associated with an endocytic zone. Moreover, a mutation in SHANK2 found in autism spectrum disorders (ASDs) similarly disrupts these processes. On the basis of these findings, we propose that synaptic Shank scaffolds anchor the endocytic machinery to govern the efficient trafficking of mGluR5 and to balance the surface expression of mGluRs to efficiently modulate neuronal functioning

Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5

Activation of postsynaptic metabotropic glutamate receptors (mGluRs) modulates neuronal excitability and synaptic plasticity, while deregulation of mGluR signaling has been implicated in neurodevelopmental disorders. Overstimulation of mGluRs is restricted by the rapid endocytosis of receptors after activation. However, how membrane trafficking of mGluRs at synapses is controlled remains poorly defined. We find that in hippocampal neurons, the agonist-induced receptor internalization of synaptic mGluR5 is significantly reduced in Shank knockdown neurons. This is rescued by the re-expression of wild-type Shanks, but not by mutants unable to bind Homer1b/c, Dynamin2, or Cortactin. These effects are paralleled by a reduction in synapses associated with an endocytic zone. Moreover, a mutation in SHANK2 found in autism spectrum disorders (ASDs) similarly disrupts these processes. On the basis of these findings, we propose that synaptic Shank scaffolds anchor the endocytic machinery to govern the efficient trafficking of mGluR5 and to balance the surface expression of mGluRs to efficiently modulate neuronal functioning

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

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

Overview plots for top <i>cis</i> eQTLs.

<p>An overview of the 4 most significant <i>cis</i> eQTLs: rs11150882 with <i>C17orf97</i> (panel A), rs11158569 with <i>CHURC1</i> (panel B), rs2779212 with <i>ZSWIM7</i> (panel C) and rs2549794 with <i>ERAP2</i> (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.</p

eQTL overview plots for 4 cardiac trait GWAS candidate genes.

<p>An overview of 4 GWAS <i>cis</i> eQTLs: rs9912468 with <i>PRKCA</i> (panel A), rs7912445 with <i>GNB4</i> (panel B), rs8049607 with <i>LITAF</i> (panel C) and rs6882776 with <i>NKX2-5</i> (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.</p

Overview of the 30 most significant <i>cis</i> eQTLs, reported as independent LD-pruned SNP clusters (see Materials & Methods).

<p>The MAF and beta (effect size per copy of the minor allele) for the most significant SNP of each cluster is listed. LD  =  linkage disequilibrium, TSS  =  transcription start site, Chr.  =  chromosome.</p

Look-up of SNPs from cardiac GWAS in eQTL data.

<p>Overview of eQTL effects of reported cardiac electric trait related GWAS SNPs. Only GWAS SNPs reaching genome-wide significance as stated in the original studies (p-value ≤5×10⁻⁸) and with nominal eQTL association (p≤0.05) are reported. This resulted in 34 independent loci. <i>PRKCA</i> (<i>rs9912468</i>, QRS duration) reaches genome-wide significance (4×10⁻⁸; represented in bold in table). The beta is defined as the effect size per copy of the minor allele. LD  =  linkage disequilibrium, TSS  =  transcription start site, Chr.  =  chromosome, Y  =  yes, N  =  no.</p