Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.
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 m...
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Public Library of Science (PLoS)
2011-12-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002367&type=printable |
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| author | Maxime Rotival Tanja Zeller Philipp S Wild Seraya Maouche Silke Szymczak Arne Schillert Raphaele Castagné Arne Deiseroth Carole Proust Jessy Brocheton Tiphaine Godefroy Claire Perret Marine Germain Medea Eleftheriadis Christoph R Sinning Renate B Schnabel Edith Lubos Karl J Lackner Heidi Rossmann Thomas Münzel Augusto Rendon Cardiogenics Consortium Jeanette Erdmann Panos Deloukas Christian Hengstenberg Patrick Diemert Gilles Montalescot Willem H Ouwehand Nilesh J Samani Heribert Schunkert David-Alexandre Tregouet Andreas Ziegler Alison H Goodall François Cambien Laurence Tiret Stefan Blankenberg |
| author_facet | Maxime Rotival Tanja Zeller Philipp S Wild Seraya Maouche Silke Szymczak Arne Schillert Raphaele Castagné Arne Deiseroth Carole Proust Jessy Brocheton Tiphaine Godefroy Claire Perret Marine Germain Medea Eleftheriadis Christoph R Sinning Renate B Schnabel Edith Lubos Karl J Lackner Heidi Rossmann Thomas Münzel Augusto Rendon Cardiogenics Consortium Jeanette Erdmann Panos Deloukas Christian Hengstenberg Patrick Diemert Gilles Montalescot Willem H Ouwehand Nilesh J Samani Heribert Schunkert David-Alexandre Tregouet Andreas Ziegler Alison H Goodall François Cambien Laurence Tiret Stefan Blankenberg |
| author_sort | Maxime Rotival |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1a2e314eb5264c0da8eb2cd82c7bb6eb |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2011-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-1a2e314eb5264c0da8eb2cd82c7bb6eb2025-08-20T02:05:36ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-12-01712e100236710.1371/journal.pgen.1002367Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.Maxime RotivalTanja ZellerPhilipp S WildSeraya MaoucheSilke SzymczakArne SchillertRaphaele CastagnéArne DeiserothCarole ProustJessy BrochetonTiphaine GodefroyClaire PerretMarine GermainMedea EleftheriadisChristoph R SinningRenate B SchnabelEdith LubosKarl J LacknerHeidi RossmannThomas MünzelAugusto RendonCardiogenics ConsortiumJeanette ErdmannPanos DeloukasChristian HengstenbergPatrick DiemertGilles MontalescotWillem H OuwehandNilesh J SamaniHeribert SchunkertDavid-Alexandre TregouetAndreas ZieglerAlison H GoodallFrançois CambienLaurence TiretStefan BlankenbergOne 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002367&type=printable |
| spellingShingle | Maxime Rotival Tanja Zeller Philipp S Wild Seraya Maouche Silke Szymczak Arne Schillert Raphaele Castagné Arne Deiseroth Carole Proust Jessy Brocheton Tiphaine Godefroy Claire Perret Marine Germain Medea Eleftheriadis Christoph R Sinning Renate B Schnabel Edith Lubos Karl J Lackner Heidi Rossmann Thomas Münzel Augusto Rendon Cardiogenics Consortium Jeanette Erdmann Panos Deloukas Christian Hengstenberg Patrick Diemert Gilles Montalescot Willem H Ouwehand Nilesh J Samani Heribert Schunkert David-Alexandre Tregouet Andreas Ziegler Alison H Goodall François Cambien Laurence Tiret Stefan Blankenberg Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. PLoS Genetics |
| title | Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. |
| title_full | Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. |
| title_fullStr | Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. |
| title_full_unstemmed | Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. |
| title_short | Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. |
| title_sort | integrating genome wide genetic variations and monocyte expression data reveals trans regulated gene modules in humans |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002367&type=printable |
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