Integrating Genome-Wide Genetic Variations and Monocyte Expression Data Reveals Trans-Regulated Gene Modules in Humans

被引：102

作者：

Rotival, Maxime ^{[1
,2
]}

Zeller, Tanja ^{[3
]}

Wild, Philipp S. ^{[3
]}

Maouche, Seraya ^{[4
]}

Szymczak, Silke ^{[5
]}

Schillert, Arne ^{[3
,5
]}

Castagne, Raphaele ^{[1
,2
]}

Deiseroth, Arne

Proust, Carole ^{[1
,2
]}

Brocheton, Jessy ^{[1
,2
]}

Godefroy, Tiphaine ^{[1
,2
]}

Perret, Claire ^{[1
,2
]}

Germain, Marine ^{[1
,2
]}

Eleftheriadis, Medea ^{[3
]}

Sinning, Christoph R. ^{[3
]}

Schnabel, Renate B. ^{[3
]}

Lubos, Edith ^{[3
]}

Lackner, Karl J. ^{[6
]}

Rossmann, Heidi ^{[6
]}

Muenzel, Thomas ^{[3
]}

Rendon, Augusto ^{[7
,8
,10
]}

Erdmann, Jeanette ^{[4
]}

Deloukas, Panos ^{[9
]}

Hengstenberg, Christian ^{[11
]}

Diemert, Patrick ^{[4
]}

Montalescot, Gilles ^{[1
,2
]}

Ouwehand, Willem H. ^{[7
,8
,9
]}

Samani, Nilesh J. ^{[12
,13
]}

Schunkert, Heribert ^{[4
]}

Tregouet, David-Alexandre ^{[1
,2
]}

Ziegler, Andreas ^{[5
]}

Goodall, Alison H. ^{[12
,13
]}

Cambien, Francois ^{[1
,2
]}

Tiret, Laurence ^{[1
,2
]}

Blankenberg, Stefan ^{[3
]}

机构：

[1] Univ Paris 06, INSERM, UMRS 937, Paris, France

[2] Sch Med, Paris, France

[3] Johannes Gutenberg Univ Mainz, Med Klin & Poliklin 2, Univ Med, D-6500 Mainz, Germany

[4] Univ Lubeck, Med Klin 2, Lubeck, Germany

[5] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany

[6] Johannes Gutenberg Univ Mainz, Univ Med, Inst Klin Chem & Lab Med, Mainz, Germany

[7] Univ Cambridge, Dept Haematol, Cambridge, England

[8] Natl Hlth Serv Blood & Transplant, Cambridge, England

[9] Wellcome Trust Sanger Inst, Hinxton, England

[10] MRC Biostat Unit, Cambridge, England

[11] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany

[12] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[13] Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester, Leics, England

来源：

PLOS GENETICS | 2011年 / 7卷 / 12期

关键词：

INDEPENDENT COMPONENT ANALYSIS; QUANTITATIVE TRAIT LOCI; NONOBESE DIABETIC MICE; IMMUNE-RESPONSE; DISEASE; ASSOCIATION; DISCOVERY; NETWORKS; SUSCEPTIBILITY; TRANSCRIPTION;

D O I：

10.1371/journal.pgen.1002367

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：13

共 57 条

[1] Deconvolution of Blood Microarray Data Identifies Cellular Activation Patterns in Systemic Lupus Erythematosus [J].

Abbas, Alexander R. ;

Wolslegel, Kristen ;

Seshasayee, Dhaya ;

Modrusan, Zora ;

Clark, Hilary F. .

PLOS ONE, 2009, 4 (07)

[2] GenABEL: an R library for genome-wide association analysis [J].

Aulchenko, Yurii S. ;

Ripke, Stephan ;

Isaacs, Aaron ;

Van Duijn, Cornelia M. .

BIOINFORMATICS, 2007, 23 (10) :1294-1296

[3] Systems genetics of complex traits in Drosophila melanogaster [J].

Ayroles, Julien F. ;

Carbone, Mary Anna ;

Stone, Eric A. ;

Jordan, Katherine W. ;

Lyman, Richard F. ;

Magwire, Michael M. ;

Rollmann, Stephanie M. ;

Duncan, Laura H. ;

Lawrence, Faye ;

Anholt, Robert R. H. ;

Mackay, Trudy F. C. .

NATURE GENETICS, 2009, 41 (03) :299-307

[4] Mapping gene expression quantitative trait loci by singular value decomposition and independent component analysis [J].

Biswas, Shameek ;

Storey, John D. ;

Akey, Joshua M. .

BMC BIOINFORMATICS, 2008, 9 (1)

[5] Metagenes and molecular pattern discovery using matrix factorization [J].

Brunet, JP ;

Tamayo, P ;

Golub, TR ;

Mesirov, JP .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (12) :4164-4169

[6] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[7] The operons, a criterion to compare the reliability of transcriptome analysis tools:: ICA is more reliable than ANOVA, PLS and PCA [J].

Carpentier, AS ;

Riva, A ;

Tisseur, P ;

Didier, G ;

Hénaut, A .

COMPUTATIONAL BIOLOGY AND CHEMISTRY, 2004, 28 (01) :3-10

[8] Variations in DNA elucidate molecular networks that cause disease [J].

Chen, Yanqing ;

Zhu, Jun ;

Lum, Pek Yee ;

Yang, Xia ;

Pinto, Shirly ;

MacNeil, Douglas J. ;

Zhang, Chunsheng ;

Lamb, John ;

Edwards, Stephen ;

Sieberts, Solveig K. ;

Leonardson, Amy ;

Castellini, Lawrence W. ;

Wang, Susanna ;

Champy, Marie-France ;

Zhang, Bin ;

Emilsson, Valur ;

Doss, Sudheer ;

Ghazalpour, Anatole ;

Horvath, Steve ;

Drake, Thomas A. ;

Lusis, Aldons J. ;

Schadt, Eric E. .

NATURE, 2008, 452 (7186) :429-435

[9] Mapping complex disease traits with global gene expression [J].

Cookson, William ;

Liang, Liming ;

Abecasis, Goncalo ;

Moffatt, Miriam ;

Lathrop, Mark .

NATURE REVIEWS GENETICS, 2009, 10 (03) :184-194

[10] A genome-wide association study of global gene expression [J].

Dixon, Anna L. ;

Liang, Liming ;

Moffatt, Miriam F. ;

Chen, Wei ;

Heath, Simon ;

Wong, Kenny C. C. ;

Taylor, Jenny ;

Burnett, Edward ;

Gut, Ivo ;

Farrall, Martin ;

Lathrop, G. Mark ;

Abecasis, Goncalo R. ;

Cookson, William O. C. .

NATURE GENETICS, 2007, 39 (10) :1202-1207

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