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Dissecting Non-Coding GWAS Loci with High-Resolution 3D Chromatin Interactions Reveals Causal Genes with Relevance to Heart Failure [Hi-C]

ABSTRACT: Dissecting Non-Coding GWAS Loci with High-Resolution 3D Chromatin Interactions Reveals Causal Genes with Relevance to Heart Failure [Hi-C]

PROVIDER: PRJNA1183891 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31291600_1.fastq.gz	Fastqsanger.gz
	SRR31291600_2.fastq.gz	Fastqsanger.gz
	SRR31291601_1.fastq.gz	Fastqsanger.gz
	SRR31291601_2.fastq.gz	Fastqsanger.gz
	SRR31291602_1.fastq.gz	Fastqsanger.gz

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Project description:Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2,112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters, and enrichment of co-localised functional elements. We found eQTLs for about 85% of analysed genes, 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 MB to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might often be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels, and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. We show for strongly heritable transcripts that a considerable gap still exists between total heritability resulting from all trans-chromosomes and explained variance of all identified trans-eSNPs. In contrast, the vast majority of most cis-heritability of these genes is already explained. Dissection of co-localised functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene-expression, pathways and disease related processes. Gene expression from human blood mononuclear cells from individuals of the Leipzig LIFE Heart Study was analyzed applying Illumina HT-12 v4 Expression BeadChips. After preprocessing, 28,295 expression probes for 2,112 individuals remained for analysis. In a population-based analysis, we identified associations between DNA variants and RNA expression levels and characterized these findings.

Dataset Information

Dissecting Non-Coding GWAS Loci with High-Resolution 3D Chromatin Interactions Reveals Causal Genes with Relevance to Heart Failure [Hi-C]

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