title: 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.
  
  
  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.
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, München, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schramm
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Marzi
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Carstensen
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Eva
authors.initials: E
authors.lastname: Reinmaa
authors.affiliation: Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Biffar
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Eckstein
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Department of Psychiatry and Psychotherapy, Helios Hospital Stralsund, University Medicine of Greifswald, Greifswald, Germany.
authors.forename: Hans-Jörgen
authors.initials: HJ
authors.lastname: Grabe
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Kastenmüller
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia; Estonian Biocentre, Tartu, Estonia.
authors.forename: Evelin
authors.initials: E
authors.lastname: Mihailov
authors.affiliation: Institute of Human Genetics, Technical University Munich, München, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Greifswald, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Petersmann
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Germany; Division of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität Munich, Neuherberg, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang-Sattler
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, München, Germany; Munich Heart Alliance, München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, München, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
mesh_terms: D001769:Blood / Q000378:metabolism*; D002874:Chromosome Mapping; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D005819:Genetic Markers; D006801:Humans; D016014:Linear Models; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D005819:Genetic Markers
references.citation: PLoS Genet. 2011 Feb 03;7(2):e1002003
references.pmid: 21304890
references.citation: Hum Mutat. 2008 Feb;29(2):315-22
references.pmid: 17994548
references.citation: Nat Genet. 2007 Oct;39(10):1217-24
references.pmid: 17873874
references.citation: Nat Genet. 2007 Oct;39(10):1202-7
references.pmid: 17873877
references.citation: Nat Rev Genet. 2012 Nov;13(11):759-69
references.pmid: 23032255
references.citation: Science. 2009 Sep 4;325(5945):1246-50
references.pmid: 19644074
references.citation: Diabet Med. 2009 Dec;26(12):1212-9
references.pmid: 20002472
references.citation: Gesundheitswesen. 2005 Aug;67 Suppl 1:S19-25
references.pmid: 16032513
references.citation: Nat Genet. 2010 Jan;42(1):53-61
references.pmid: 20010836
references.citation: Nature. 2011 Aug 31;477(7362):54-60
references.pmid: 21886157
references.citation: Nat Genet. 2006 Nov;38(11):1348-54
references.pmid: 17033623
references.citation: Int J Epidemiol. 2011 Apr;40(2):294-307
references.pmid: 20167617
references.citation: Nat Genet. 2010 Feb;42(2):137-41
references.pmid: 20037589
references.citation: Nat Genet. 2010 May;42(5):373-5
references.pmid: 20383145
references.citation: Nat Genet. 2011 Sep 11;43(10):1005-11
references.pmid: 21909110
references.citation: Am J Hum Genet. 2010 Dec 10;87(6):779-89
references.pmid: 21129726
references.citation: Nat Genet. 2009 Nov;41(11):1182-90
references.pmid: 19820697
references.citation: PLoS One. 2012;7(12):e50938
references.pmid: 23236413
references.citation: Hugo J. 2011 Dec;5(1-4):13-23
references.pmid: 23205161
references.citation: Eur J Hum Genet. 2013 Jan;21(1):48-54
references.pmid: 22692066
references.citation: Nat Genet. 2010 May;42(5):376-84
references.pmid: 20383146
references.citation: PLoS Genet. 2012;8(3):e1002607
references.pmid: 22479202
references.citation: PLoS One. 2010 May 18;5(5):e10693
references.pmid: 20502693
references.citation: Am J Hypertens. 2010 Sep;23(9):1014-22
references.pmid: 20725057
references.citation: BMC Res Notes. 2012 Jan 04;5:1
references.pmid: 22214347
references.citation: PLoS Genet. 2013 May;9(5):e1003486
references.pmid: 23671422
references.citation: PLoS Genet. 2012;8(11):e1003029
references.pmid: 23209423
references.citation: PLoS One. 2013;8(1):e54967
references.pmid: 23359819
references.citation: J Allergy Clin Immunol. 2012 May;129(5):1218-28
references.pmid: 22424883
references.citation: Genome Res. 2012 Mar;22(3):456-66
references.pmid: 22183966
references.citation: PLoS Genet. 2011 May;7(5):e1002078
references.pmid: 21637794
references.citation: PLoS Genet. 2011 Aug;7(8):e1002197
references.pmid: 21829388
references.citation: Nat Genet. 2008 May;40(5):609-15
references.pmid: 18391951
references.citation: Am J Hum Genet. 2009 Jan;84(1):66-71
references.pmid: 19110211
references.citation: Nat Genet. 2012 Mar 25;44(5):502-10
references.pmid: 22446964
references.citation: PLoS Biol. 2008 May 6;6(5):e107
references.pmid: 18462017