Systematic identification of trans eQTLs as putative drivers of known disease associations

被引：1266

作者：

Westra, Harm-Jan ^{[1
]}

Peters, Marjolein J. ^{[2
,3
,4
]}

Esko, Tonu ^{[5
]}

Yaghootkar, Hanieh ^{[6
]}

Schurmann, Claudia ^{[7
]}

Kettunen, Johannes ^{[8
,9
]}

Christiansen, Mark W. ^{[10
]}

Fairfax, Benjamin P. ^{[11
,12
]}

Schramm, Katharina ^{[13
,14
]}

Powell, Joseph E. ^{[15
,16
]}

Zhernakova, Alexandra ^{[1
]}

Zhernakova, Daria V. ^{[1
]}

Veldink, Jan H. ^{[17
]}

Van den Berg, Leonard H. ^{[17
]}

Karjalainen, Juha ^{[1
]}

Withoff, Sebo ^{[1
]}

Uitterlinden, Andre G. ^{[2
,3
,4
,18
]}

Hofman, Albert ^{[3
,4
,18
]}

Rivadeneira, Fernando ^{[2
,3
,4
,18
]}

't Hoen, Peter A. C. ^{[19
]}

Reinmaa, Eva ^{[5
]}

Fischer, Krista ^{[5
]}

Nelis, Mari ^{[5
]}

Milani, Lili ^{[5
]}

Melzer, David ^{[20
]}

Ferrucci, Luigi ^{[21
]}

Singleton, Andrew B. ^{[22
]}

Hernandez, Dena G. ^{[22
,23
]}

Nalls, Michael A. ^{[22
]}

Homuth, Georg ^{[7
]}

Nauck, Matthias ^{[24
]}

Radke, Doerte ^{[25
]}

Voelker, Uwe ^{[7
]}

Perola, Markus ^{[5
,9
]}

Salomaa, Veikko ^{[9
]}

Brody, Jennifer ^{[10
]}

Suchy-Dicey, Astrid ^{[26
]}

Gharib, Sina A. ^{[27
]}

Enquobahrie, Daniel A. ^{[26
]}

Lumley, Thomas ^{[28
]}

Montgomery, Grant W. ^{[29
]}

Makino, Seiko ^{[11
]}

Prokisch, Holger ^{[13
,14
]}

Herder, Christian ^{[30
]}

Roden, Michael ^{[30
,31
,32
]}

Grallert, Harald ^{[33
]}

Meitinger, Thomas ^{[13
,14
,34
,35
]}

Strauch, Konstantin ^{[36
,37
]}

Li, Yang ^{[38
]}

Jansen, Ritsert C. ^{[38
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[2] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[3] Netherlands Genom Initiat Sponsored Netherlands C, Leiden, Netherlands

[4] Netherlands Genom Initiat Sponsored Netherlands C, Rotterdam, Netherlands

[5] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[6] Univ Exeter, Sch Med, Exeter, Devon, England

[7] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany

[8] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[9] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland

[10] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[11] Wellcome Trust Ctr Human Genet, Oxford, England

[12] Churchill Hosp, Canc & Haematol Ctr, Dept Oncol, Oxford OX3 7LJ, England

[13] Helmholz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany

[14] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany

[15] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia

[16] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

[17] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, Utrecht, Netherlands

[18] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[19] Leiden Univ Med Ctr, Ctr Human & Clin Genet, Leiden, Netherlands

[20] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England

[21] NIA, Clin Res Branch, Adv Studies Translat Res Aging ASTRA Unit, Harbor Hosp, Baltimore, MD 21224 USA

[22] NIA, Neurogenet Lab, US NIH, Bethesda, MD 20892 USA

[23] UCL, Inst Neurol, Reta Lila Labs, Dept Mol Neurosci, London, England

[24] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[25] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[26] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[27] Univ Washington, Ctr Lung Biol, Dept Med, Div Pulm & Crit Care Med,Computat Med Core, Seattle, WA 98195 USA

[28] Univ Auckland, Dept Stat, Auckland 1, New Zealand

[29] Queensland Inst Med Res, Herston, Qld 4006, Australia

[30] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, D-40225 Dusseldorf, Germany

[31] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, D-40225 Dusseldorf, Germany

[32] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Metab Dis, D-40225 Dusseldorf, Germany

[33] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany

[34] German Ctr Cardiovasc Res DZHK, Gottingen, Germany

[35] Munich Heart Alliance, Munich, Germany

[36] Univ Munich, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany

[37] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany

[38] Univ Groningen, Groningen Bioinformat Ctr, Groningen, Netherlands

[39] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA

[40] Wellcome Trust Res Labs, Sanger Inst, Cambridge, England

来源：

NATURE GENETICS | 2013年 / 45卷 / 10期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; SUSCEPTIBILITY LOCI; INTERFERON; RISK; VARIANTS; POLYMORPHISMS; CELLS; CIS; C1Q;

D O I：

10.1038/ng.2756

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE)(1), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE2-4. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.

引用

页码：1238 / U195

页数：8

共 59 条

[1] Sequence Polymorphisms Cause Many False cis eQTLs [J].

Alberts, Rudi ;

Terpstra, Peter ;

Li, Yang ;

Breitling, Rainer ;

Nap, Jan-Peter ;

Jansen, Ritsert C. .

PLOS ONE, 2007, 2 (07)

[2] A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[3] Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus [J].

Baechler, EC ;

Batliwalla, FM ;

Karypis, G ;

Gaffney, PM ;

Ortmann, WA ;

Espe, KJ ;

Shark, KB ;

Grande, WJ ;

Hughes, KM ;

Kapur, V ;

Gregersen, PK ;

Behrens, TW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (05) :2610-2615

[4] Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes [J].

Barrett, Jeffrey C. ;

Clayton, David G. ;

Concannon, Patrick ;

Akolkar, Beena ;

Cooper, Jason D. ;

Erlich, Henry A. ;

Julier, Cecile ;

Morahan, Grant ;

Nerup, Jorn ;

Nierras, Concepcion ;

Plagnol, Vincent ;

Pociot, Flemming ;

Schuilenburg, Helen ;

Smyth, Deborah J. ;

Stevens, Helen ;

Todd, John A. ;

Walker, Neil M. ;

Rich, Stephen S. .

NATURE GENETICS, 2009, 41 (06) :703-707

[5] Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies [J].

Bengtsson, AA ;

Sturfelt, G ;

Truedsson, L ;

Blomberg, J ;

Alm, G ;

Vallin, H ;

Rönnblom, L .

LUPUS, 2000, 9 (09) :664-671

[6] Interferon and granulopoiesis signatures in systemic lupus erythematosus blood [J].

Bennett, L ;

Palucka, AK ;

Arce, E ;

Cantrell, V ;

Borvak, J ;

Banchereau, J ;

Pascual, V .

JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 197 (06) :711-723

[7] Effect of polymorphisms within probe-target sequences on olignonucleotide microarray experiments [J].

Benovoy, David ;

Kwan, Tony ;

Majewski, Jacek .

NUCLEIC ACIDS RESEARCH, 2008, 36 (13) :4417-4423

[8] Complement proteins C1q and MBL are pattern recognition molecules that signal immediate and long-term protective immune functions [J].

Bohlson, Suzanne S. ;

Fraser, Deborah A. ;

Tenner, Andrea J. .

MOLECULAR IMMUNOLOGY, 2007, 44 (1-3) :33-43

[9] Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies [J].

Botto, M ;

Dell'Agnola, C ;

Bygrave, AE ;

Thompson, EM ;

Cook, HT ;

Petry, F ;

Loos, M ;

Pandolfi, PP ;

Walport, MJ .

NATURE GENETICS, 1998, 19 (01) :56-59

[10] Genetical Genomics: Spotlight on QTL Hotspots [J].

Breitling, Rainer ;

Li, Yang ;

Tesson, Bruno M. ;

Fu, Jingyuan ;

Wu, Chunlei ;

Wiltshire, Tim ;

Gerrits, Alice ;

Bystrykh, Leonid V. ;

de Haan, Gerald ;

Su, Andrew I. ;

Jansen, Ritsert C. .

PLOS GENETICS, 2008, 4 (10)

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