Dataset Information

Mapping the genetic architecture of gene regulation in whole blood.

ABSTRACT:

Background

We aimed to assess whether whole blood expression quantitative trait loci (eQTLs) with effects in cis and trans are robust and can be used to identify regulatory pathways affecting disease susceptibility.

Materials and methods

We performed whole-genome eQTL analyses in 890 participants of the KORA F4 study and in two independent replication samples (SHIP-TREND, N?=?976 and EGCUT, N?=?842) using linear regression models and Bonferroni correction.

Results

In the KORA F4 study, 4,116 cis-eQTLs (defined as SNP-probe pairs where the SNP is located within a 500 kb window around the transcription unit) and 94 trans-eQTLs reached genome-wide significance and overall 91% (92% of cis-, 84% of trans-eQTLs) were confirmed in at least one of the two replication studies. Different study designs including distinct laboratory reagents (PAXgene™ vs. Tempus™ tubes) did not affect reproducibility (separate overall replication overlap: 78% and 82%). Immune response pathways were enriched in cis- and trans-eQTLs and significant cis-eQTLs were partly coexistent in other tissues (cross-tissue similarity 40-70%). Furthermore, four chromosomal regions displayed simultaneous impact on multiple gene expression levels in trans, and 746 eQTL-SNPs have been previously reported to have clinical relevance. We demonstrated cross-associations between eQTL-SNPs, gene expression levels in trans, and clinical phenotypes as well as a link between eQTLs and human metabolic traits via modification of gene regulation in cis.

Conclusions

Our data suggest that whole blood is a robust tissue for eQTL analysis and may be used both for biomarker studies and to enhance our understanding of molecular mechanisms underlying gene-disease associations.

SUBMITTER: Schramm K

PROVIDER: S-EPMC3989189 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Mapping the genetic architecture of gene regulation in whole blood.

Schramm Katharina K Marzi Carola C Schurmann Claudia C Carstensen Maren M Reinmaa Eva E Biffar Reiner R Eckstein Gertrud G Gieger Christian C Grabe Hans-Jörgen HJ Homuth Georg G Kastenmüller Gabriele G Mägi Reedik R Metspalu Andres A Mihailov Evelin E Peters Annette A Petersmann Astrid A Roden Michael M Strauch Konstantin K Suhre Karsten K Teumer Alexander A Völker Uwe U Völzke Henry H Wang-Sattler Rui R Waldenberger Melanie M Meitinger Thomas T Illig Thomas T Herder Christian C Grallert Harald H Prokisch Holger H

PloS one 20140416 4

<h4>Background</h4>We aimed to assess whether whole blood expression quantitative trait loci (eQTLs) with effects in cis and trans are robust and can be used to identify regulatory pathways affecting disease susceptibility.<h4>Materials and methods</h4>We performed whole-genome eQTL analyses in 890 participants of the KORA F4 study and in two independent replication samples (SHIP-TREND, N = 976 and EGCUT, N = 842) using linear regression models and Bonferroni correction.<h4>Results</h4>In the KO ...[more]

PMID: 24740359

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Project description:Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.

Dataset Information

Mapping the genetic architecture of gene regulation in whole blood.

Background

Materials and methods

Results

Conclusions

Publications

Mapping the genetic architecture of gene regulation in whole blood.

Similar Datasets

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