PMID: identifiant
de la référence Pubmed : |
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 (22144904)  |
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| titre : |
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Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. |
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| auteur(s) : |
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Maxime Rotival1, Tanja Zeller2, Philipp Wild2, Seraya Maouche3, Silke Szymczak4, Arne Schillert4, Raphaele Castagné1, Arne Deiseroth2, Carole Proust1, Jessy Brocheton1, Tiphaine Godefroy1, Claire Perret1, Marine Germain1, Medea Eleftheriadis2, Christoph Sinning2, Renate Schnabel2, Edith Lubos2, Karl Lackner5, Heidi Rossmann5, Thomas Münzel2, Augusto Rendon6, 7, Jeanette Erdmann3, Panos Deloukas8, Christian Hengstenberg9, Patrick Diemert3, Gilles Montalescot1, Willem Ouwehand6, 8, Nilesh Samani10, 11, Heribert Schunkert3, David-Alexandre Tregouet1, Andreas Ziegler4, Alison Goodall10, 11, François Cambien1, Laurence Tiret ( ) 1, Stefan Blankenberg2 |
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| laboratoire : |
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| résumé : |
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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. |
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| domaine : |
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Sciences du Vivant/Génétique
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langue du texte
intégral : |
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Anglais |
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| ISSN : |
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1553-7390 |
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| type de publication : |
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Articles dans des revues avec comité de lecture |
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| DOI : |
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10.1371/journal.pgen.1002367 |
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| journal : |
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| Audience : |
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internationale |
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| date de publication : |
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12/2011 |
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date de publication
électronique : |
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01/12/2011 |
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| volume : |
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7 |
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| numéro : |
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12 |
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| page, identifiant, ... : |
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e1002367 |
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| Descripteur(s) MeSH : |
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Adult – Aged – Celiac Disease – Diabetes Mellitus – Type 1 – Female – Gene Expression Profiling – Gene Expression Regulation – Genetic Predisposition to Disease – Genetic Variation – Genome – Human – Genome-Wide Association Study – Humans – Hypertension – Male – Middle Aged – Monocytes – Muramidase – Polymorphism – Single Nucleotide – Proteins – Quantitative Trait Loci – Ribosomal Proteins – Transcription Factors |
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| contrat, financement : |
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The Gutenberg Health Study is funded through the government of Rheinland-Pfalz ("Stiftung Rheinland Pfalz für Innovation", contract number AZ 961-386261/733), the research programs "Wissen schafft Zukunft" and "Schwerpunkt Vaskuläre Prävention" of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the Gutenberg Health Study. Specifically, the research reported in this article was supported by the National Genome Network "NGFNplus" by the Federal Ministry of Education and Research, Germany (contract number project A3 01GS0833), and by joint funding from the Federal Ministry of Education and Research, Germany (contract BMBF 01KU0908A), and from the Agence Nationale de la Recherche, France (contract ANR 09 GENO 106 01), for the project CARDomics. The Cardiogenics Consortium (http://www.cardiogenics.eu/web/) is funded by the 6th Framework Program of the European Union (LSHM-CT-2006-037593). NJ Samani holds a Chair supported by the British Heart Foundation. |
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