Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.

6533b855fe1ef96bd12b0958

RESEARCH PRODUCT

Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.

Heidi Rossmann Andreas Ziegler Patrick Diemert Willem H. Ouwehand Willem H. Ouwehand Claire Perret Philipp S. Wild Augusto Rendon Raphaële Castagné François Cambien Christian Hengstenberg Medea S. Eleftheriadis C. Sinning Maxime Rotival Arne Schillert Panos Deloukas Renate B. Schnabel Edith Lubos Tiphaine Godefroy Marine Germain Laurence Tiret Silke Szymczak Seraya Maouche Heribert Schunkert Carole Proust David-alexandre Trégouët Blankenberg Stefan Tanja Zeller Jeanette Erdmann Thomas Münzel Alison H. Goodall Karl J. Lackner Jessy Brocheton Arne Deiseroth Nilesh J. Samani Gilles Montalescot

subject

Male Cancer Research Gene Expression Genome-wide association study Genetic Networks Coronary Artery Disease [SDV.GEN] Life Sciences [q-bio]/Genetics Cardiovascular MESH: Monocytes Monocytes MESH: Hypertension Transcriptomes 0302 clinical medicine MESH: Proteins MESH: Genetic Variation Genetics (clinical)Genetics MESH: Aged 0303 health sciences education.field_of_study MESH: Middle Aged MESH: Polymorphism Single Nucleotide Intracellular Signaling Peptides and Proteins MESH: Genetic Predisposition to Disease Genomics MESH: Transcription Factors Middle Aged MESH: Ribosomal Proteins MESH: Gene Expression Regulation 3. Good health Hypertension Medicine Female MESH: Diabetes Mellitus Type 1 Research Article Adult Ribosomal Proteins lcsh:QH426-470 Population Quantitative Trait Loci Locus (genetics)Single-nucleotide polymorphism Biology Quantitative trait locus Polymorphism Single Nucleotide 03 medical and health sciences MESH: Gene Expression Profiling Genome Analysis Tools Genetics Genome-Wide Association Studies Humans Genetic Predisposition to Disease Gene Networks education Molecular Biology Biology Ecology Evolution Behavior and Systematics MESH: Genome Human 030304 developmental biology Genetic association Adaptor Proteins Signal Transducing Aged [SDV.GEN]Life Sciences [q-bio]/Genetics MESH: Humans Genome Human Gene Expression Profiling Genetic Variation Proteins Human Genetics MESH: Adult Atherosclerosis MESH: Male MESH: Quantitative Trait Loci Gene expression profiling Celiac Disease lcsh:Genetics Diabetes Mellitus Type 1 Gene Expression Regulation Expression quantitative trait loci Genetics of Disease MESH: Genome-Wide Association Study MESH: Muramidase Muramidase Genome Expression Analysis MESH: Female 030217 neurology & neurosurgery MESH: Celiac Disease Genome-Wide Association Study Transcription Factors

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.

year	journal	country	edition	language
2011-12-01

10.1371/journal.pgen.1002367 https://www.hal.inserm.fr/inserm-00711658