title: Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.
abstract: One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns-independent component analysis-to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease.
authors.affiliation: INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Rotival
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Wild
authors.forename: Seraya
authors.initials: S
authors.lastname: Maouche
authors.forename: Silke
authors.initials: S
authors.lastname: Szymczak
authors.forename: Arne
authors.initials: A
authors.lastname: Schillert
authors.forename: Raphaele
authors.initials: R
authors.lastname: Castagné
authors.forename: Arne
authors.initials: A
authors.lastname: Deiseroth
authors.forename: Carole
authors.initials: C
authors.lastname: Proust
authors.forename: Jessy
authors.initials: J
authors.lastname: Brocheton
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Godefroy
authors.forename: Claire
authors.initials: C
authors.lastname: Perret
authors.forename: Marine
authors.initials: M
authors.lastname: Germain
authors.forename: Medea
authors.initials: M
authors.lastname: Eleftheriadis
authors.forename: Christoph R
authors.initials: CR
authors.lastname: Sinning
authors.forename: Renate B
authors.initials: RB
authors.lastname: Schnabel
authors.forename: Edith
authors.initials: E
authors.lastname: Lubos
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: Heidi
authors.initials: H
authors.lastname: Rossmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Augusto
authors.initials: A
authors.lastname: Rendon
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Patrick
authors.initials: P
authors.lastname: Diemert
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Tregouet
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.forename: Laurence
authors.initials: L
authors.lastname: Tiret
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D002446:Celiac Disease / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D009113:Muramidase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C489203:RPS26 protein, human; D012269:Ribosomal Proteins; C490778:SH2B3 protein, human; D014157:Transcription Factors; C109446:YEATS4 protein, human; D009113:Muramidase; C514728:lysozyme C, human