title: Identification of context-dependent expression quantitative trait loci in whole blood.
abstract: Genetic risk factors often localize to noncoding regions of the genome with unknown effects on disease etiology. Expression quantitative trait loci (eQTLs) help to explain the regulatory mechanisms underlying these genetic associations. Knowledge of the context that determines the nature and strength of eQTLs may help identify cell types relevant to pathophysiology and the regulatory networks underlying disease. Here we generated peripheral blood RNA-seq data from 2,116 unrelated individuals and systematically identified context-dependent eQTLs using a hypothesis-free strategy that does not require previous knowledge of the identity of the modifiers. Of the 23,060 significant cis-regulated genes (false discovery rate (FDR) ≤ 0.05), 2,743 (12%) showed context-dependent eQTL effects. The majority of these effects were influenced by cell type composition. A set of 145 cis-eQTLs depended on type I interferon signaling. Others were modulated by specific transcription factors binding to the eQTL SNPs.
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Zhernakova
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Patrick
authors.identifier: 0000-0002-5654-3966
authors.initials: P
authors.lastname: Deelen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Vermaat
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Iterson
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van Galen
authors.affiliation: Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Wibowo
authors.initials: W
authors.lastname: Arindrarto
authors.affiliation: Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van 't Hof
authors.affiliation: Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Mei
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Freerk
authors.initials: F
authors.lastname: van Dijk
authors.affiliation: Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Marc Jan
authors.initials: MJ
authors.lastname: Bonder
authors.affiliation: Department of Internal Medicine, ErasmusMC, Rotterdam, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Rooij
authors.affiliation: Department of Internal Medicine, ErasmusMC, Rotterdam, the Netherlands.
authors.forename: Marijn
authors.initials: M
authors.lastname: Verkerk
authors.affiliation: Department of Internal Medicine, ErasmusMC, Rotterdam, the Netherlands.
authors.forename: P Mila
authors.initials: PM
authors.lastname: Jhamai
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Moed
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Szymon M
authors.initials: SM
authors.lastname: Kielbasa
authors.affiliation: SURFsara, Amsterdam, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Bot
authors.affiliation: SURFsara, Amsterdam, the Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Nooren
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Pool
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jenny
authors.initials: J
authors.lastname: van Dongen
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jouke J
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.|School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.|School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Carla J H
authors.initials: CJ
authors.lastname: van der Kallen
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.|School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Ettje F
authors.initials: EF
authors.lastname: Tigchelaar
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Niek
authors.initials: N
authors.lastname: de Klein
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: van Heemst
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.affiliation: Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Internal Medicine, ErasmusMC, Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.|School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Marleen M J
authors.initials: MM
authors.lastname: van Greevenbroek
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Morris A
authors.initials: MA
authors.lastname: Swertz
authors.affiliation: School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.|Genetic Epidemiology Unit, Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands.|Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands.
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.affiliation: Department of Internal Medicine, ErasmusMC, Rotterdam, the Netherlands.
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Bastiaan T
authors.initials: BT
authors.lastname: Heijmans
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
mesh_terms: D001798:Blood Proteins / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012333:RNA, Messenger / Q000097:blood* / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*
chemical_list: D001798:Blood Proteins; D012333:RNA, Messenger