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 - Consortium, Cardiogenics
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
PY - 2011/12/1
Y1 - 2011/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=84855267424&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1002367
DO - 10.1371/journal.pgen.1002367
M3 - Journal articles
C2 - 22144904
AN - SCOPUS:84855267424
SN - 1553-7390
VL - 7
JO - PLoS Genetics
JF - PLoS Genetics
IS - 12
M1 - e1002367
ER -
