Mapping the genetic architecture of gene regulation in whole blood

Katharina Schramm, Carola Marzi, Claudia Schurmann, Maren Carstensen, Eva Reinmaa, Reiner Biffar, Gertrud Eckstein, Christian Gieger, Hans Jörgen Grabe, Georg Homuth, Gabriele Kastenmüller, Reedik Mägi, Andres Metspalu, Evelin Mihailov, Annette Peters, Astrid Petersmann, Michael Roden, Konstantin Strauch, Karsten Suhre, Alexander Teumer & 9 others Uwe Völker, Henry Völzke, Rui Wang-Sattler, Melanie Waldenberger, Thomas Meitinger, Thomas Illig, Christian Herder, Harald Grallert, Holger Prokisch

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Article numbere93844
JournalPLoS One
Volume9
Issue number4
DOIs
Publication statusPublished - 16 Apr 2014
Externally publishedYes

Fingerprint

Quantitative Trait Loci
Gene expression
chromosome mapping
quantitative trait loci
Blood
Genes
Tissue
blood
genes
Biomarkers
Transcription
Single Nucleotide Polymorphism
Linear regression
Linear Models
Genome
Gene Expression
gene expression
genome
Disease Susceptibility
reproducibility

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Schramm, K., Marzi, C., Schurmann, C., Carstensen, M., Reinmaa, E., Biffar, R., ... Prokisch, H. (2014). Mapping the genetic architecture of gene regulation in whole blood. PLoS One, 9(4), [e93844]. https://doi.org/10.1371/journal.pone.0093844

Mapping the genetic architecture of gene regulation in whole blood. / Schramm, Katharina; Marzi, Carola; Schurmann, Claudia; Carstensen, Maren; Reinmaa, Eva; Biffar, Reiner; Eckstein, Gertrud; Gieger, Christian; Grabe, Hans Jörgen; Homuth, Georg; Kastenmüller, Gabriele; Mägi, Reedik; Metspalu, Andres; Mihailov, Evelin; Peters, Annette; Petersmann, Astrid; Roden, Michael; Strauch, Konstantin; Suhre, Karsten; Teumer, Alexander; Völker, Uwe; Völzke, Henry; Wang-Sattler, Rui; Waldenberger, Melanie; Meitinger, Thomas; Illig, Thomas; Herder, Christian; Grallert, Harald; Prokisch, Holger.

In: PLoS One, Vol. 9, No. 4, e93844, 16.04.2014.

Research output: Contribution to journalArticle

Schramm, K, Marzi, C, Schurmann, C, Carstensen, M, Reinmaa, E, Biffar, R, Eckstein, G, Gieger, C, Grabe, HJ, Homuth, G, Kastenmüller, G, Mägi, R, Metspalu, A, Mihailov, E, Peters, A, Petersmann, A, Roden, M, Strauch, K, Suhre, K, Teumer, A, Völker, U, Völzke, H, Wang-Sattler, R, Waldenberger, M, Meitinger, T, Illig, T, Herder, C, Grallert, H & Prokisch, H 2014, 'Mapping the genetic architecture of gene regulation in whole blood', PLoS One, vol. 9, no. 4, e93844. https://doi.org/10.1371/journal.pone.0093844
Schramm K, Marzi C, Schurmann C, Carstensen M, Reinmaa E, Biffar R et al. Mapping the genetic architecture of gene regulation in whole blood. PLoS One. 2014 Apr 16;9(4). e93844. https://doi.org/10.1371/journal.pone.0093844
Schramm, Katharina ; Marzi, Carola ; Schurmann, Claudia ; Carstensen, Maren ; Reinmaa, Eva ; Biffar, Reiner ; Eckstein, Gertrud ; Gieger, Christian ; Grabe, Hans Jörgen ; Homuth, Georg ; Kastenmüller, Gabriele ; Mägi, Reedik ; Metspalu, Andres ; Mihailov, Evelin ; Peters, Annette ; Petersmann, Astrid ; Roden, Michael ; Strauch, Konstantin ; Suhre, Karsten ; Teumer, Alexander ; Völker, Uwe ; Völzke, Henry ; Wang-Sattler, Rui ; Waldenberger, Melanie ; Meitinger, Thomas ; Illig, Thomas ; Herder, Christian ; Grallert, Harald ; Prokisch, Holger. / Mapping the genetic architecture of gene regulation in whole blood. In: PLoS One. 2014 ; Vol. 9, No. 4.
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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.",
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AU - Schramm, Katharina

AU - Marzi, Carola

AU - Schurmann, Claudia

AU - Carstensen, Maren

AU - Reinmaa, Eva

AU - Biffar, Reiner

AU - Eckstein, Gertrud

AU - Gieger, Christian

AU - Grabe, Hans Jörgen

AU - Homuth, Georg

AU - Kastenmüller, Gabriele

AU - Mägi, Reedik

AU - Metspalu, Andres

AU - Mihailov, Evelin

AU - Peters, Annette

AU - Petersmann, Astrid

AU - Roden, Michael

AU - Strauch, Konstantin

AU - Suhre, Karsten

AU - Teumer, Alexander

AU - Völker, Uwe

AU - Völzke, Henry

AU - Wang-Sattler, Rui

AU - Waldenberger, Melanie

AU - Meitinger, Thomas

AU - Illig, Thomas

AU - Herder, Christian

AU - Grallert, Harald

AU - Prokisch, Holger

PY - 2014/4/16

Y1 - 2014/4/16

N2 - 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.

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