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Allelic expression mapping across cell lineages reveal repressor disruption among disease SNPs

ABSTRACT: Most variants associated to diseases are located in non-coding regions of the genome, and are thought to be regulatory in nature. Cis-regulatory SNPs (cis-rSNPs) impacting transcription can be identified through the mapping of differences in allelic expression (AE). We mapped common cis-rSNPs of protein coding and non-coding genes in 3 distinct cell-types. We show 70% sharing across tissues and similar genetically controlled transcription for protein-coding genes and lincRNAs. Candidate cis-rSNPs altering the expression of 42 non-coding RNA overlap SNPs underlying GWAS associations for 39 diseases. We uncover a new class of cis-rSNPs leading to disruption of footprint-derived de novo motifs, predominantly bind by repressive factors and implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide proof-of-principle for a new approach for genome-wide functional validation of transcription factor – SNP interactions. We perturbed NFκB action in lymphoblasts and identified 489 cis-regulated transcripts with altered AE after NFkB perturbation. Altogether, we performed a comprehensive analysis of cis-variation in four cell-populations, and provide new tools for the identification of functional variants associated to complex diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53837 | GEO | 2014/11/03

SECONDARY ACCESSION(S): PRJNA255115

REPOSITORIES: GEO

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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.

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Allelic expression mapping across cell lineages reveal repressor disruption among disease SNPs

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