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Hum Mol Genet. 2015 Aug 15;24(16):4746-63. doi: 10.1093/hmg/ddv194. Epub 2015 May 27.

Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci†.

Author information

1
Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases, Cognitive Genetics, Department of Cell Therapy.
2
Department for Computer Science, Analysis Strategies Group, Department of Diagnostics, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and.
3
Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
4
Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases.
5
LIFE - Leipzig Research Center for Civilization Diseases, Department of Internal Medicine/Cardiology, Heart Center.
6
Interdisciplinary Center for Clinical Research, Faculty of Medicine and .
7
LIFE - Leipzig Research Center for Civilization Diseases, Institute of Laboratory Medicine, University of Leipzig, Leipzig, Germany.
8
Department for Computer Science, RNomics Group, Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology- IZI, Leipzig, Germany, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and.
9
Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases, markus.scholz@imise.uni-leipzig.de.

Abstract

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 2112 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-localized functional elements. We found eQTLs for about 85% of analysed genes, and 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 frequently 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. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized 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.

PMID:
26019233
PMCID:
PMC4512630
DOI:
10.1093/hmg/ddv194
[Indexed for MEDLINE]
Free PMC Article

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