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

TY - JOUR

T1 - Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans

AU - Rotival, Maxime

AU - Zeller, Tanja

AU - Wild, Philipp S

AU - Maouche, Seraya

AU - Szymczak, Silke

AU - Schillert, Arne

AU - Castagné, Raphaele

AU - Deiseroth, Arne

AU - Proust, Carole

AU - Brocheton, Jessy

AU - Godefroy, Tiphaine

AU - Perret, Claire

AU - Germain, Marine

AU - Eleftheriadis, Medea

AU - Sinning, Christoph R

AU - Schnabel, Renate B

AU - Lubos, Edith

AU - Lackner, Karl J

AU - Rossmann, Heidi

AU - Münzel, Thomas

AU - Rendon, Augusto

AU - Erdmann, Jeanette

AU - Deloukas, Panos

AU - Hengstenberg, Christian

AU - Diemert, Patrick

AU - Montalescot, Gilles

AU - Ouwehand, Willem H

AU - Samani, Nilesh J

AU - Schunkert, Heribert

AU - Tregouet, David-Alexandre

AU - Ziegler, Andreas

AU - Goodall, Alison H

AU - Cambien, François

AU - Tiret, Laurence

AU - Blankenberg, Stefan

AU - CardioGenics Consortium

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Adult

KW - Aged

KW - Celiac Disease/genetics

KW - Diabetes Mellitus, Type 1/genetics

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation/genetics

KW - Genetic Predisposition to Disease

KW - Genetic Variation/genetics

KW - Genome, Human

KW - Genome-Wide Association Study

KW - Humans

KW - Hypertension/genetics

KW - Intracellular Signaling Peptides and Proteins

KW - Male

KW - Middle Aged

KW - Monocytes/metabolism

KW - Muramidase/genetics

KW - Polymorphism, Single Nucleotide

KW - Proteins/genetics

KW - Quantitative Trait Loci/genetics

KW - Ribosomal Proteins/genetics

KW - Transcription Factors/genetics

U2 - 10.1371/journal.pgen.1002367

DO - 10.1371/journal.pgen.1002367

M3 - SCORING: Journal article

C2 - 22144904

VL - 7

SP - e1002367

JO - PLOS GENET

JF - PLOS GENET

SN - 1553-7404

IS - 12

ER -