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

Harm-Jan Westra; Marjolein J. Peters; Tonu Esko; Hanieh Yaghootkar; Claudia Schurmann; Johannes Kettunen; Mark W. Christiansen; Benjamin P. Fairfax; Katharina Schramm; Joseph E. Powell; Alexandra Zhernakova; Daria V. Zhernakova; Jan H. Veldink; Leonard H. Van den Berg; Juha Karjalainen; Sebo Withoff; Andre G. Uitterlinden; Albert Hofman; Fernando Rivadeneira; Peter A. C. 't Hoen; Eva Reinmaa; Krista Fischer; Mari Nelis; Lili Milani; David Melzer; Luigi Ferrucci; Andrew B. Singleton; Dena G. Hernandez; Michael A. Nalls; Georg Homuth; Matthias Nauck; Doerte Radke; Uwe Voelker; Markus Perola; Veikko Salomaa; Jennifer Brody; Astrid Suchy-Dicey; Sina A. Gharib; Daniel A. Enquobahrie; Thomas Lumley; Grant W. Montgomery; Seiko Makino; Holger Prokisch; Christian Herder; Michael Roden; Harald Grallert; Thomas Meitinger; Konstantin Strauch; Yang Li; Ritsert C. Jansen; Peter M. Visscher; Julian C. Knight; Bruce M. Psaty; Samuli Ripatti; Alexander Teumer; Timothy M. Frayling; Andres Metspalu; Joyce B. J. van Meurs; Lude Franke; Peter A.C. ’t Hoen

doi:10.1038/ng.2756

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

Harm-Jan Westra
, Marjolein J. Peters
, Tonu Esko
, Hanieh Yaghootkar
, Claudia Schurmann
, Johannes Kettunen
, Mark W. Christiansen
, Benjamin P. Fairfax
, Katharina Schramm
, Joseph E. Powell
, Alexandra Zhernakova
, Daria V. Zhernakova
, Jan H. Veldink
, Leonard H. Van den Berg
, Juha Karjalainen
, Sebo Withoff
, Andre G. Uitterlinden
, Albert Hofman
, Fernando Rivadeneira
, Peter A. C. 't Hoen

Eva Reinmaa, Krista Fischer, Mari Nelis, Lili Milani, David Melzer, Luigi Ferrucci, Andrew B. Singleton, Dena G. Hernandez, Michael A. Nalls, Georg Homuth, Matthias Nauck, Doerte Radke, Uwe Voelker, Markus Perola, Veikko Salomaa, Jennifer Brody, Astrid Suchy-Dicey, Sina A. Gharib, Daniel A. Enquobahrie, Thomas Lumley, Grant W. Montgomery, Seiko Makino, Holger Prokisch, Christian Herder, Michael Roden, Harald Grallert, Thomas Meitinger, Konstantin Strauch, Yang Li, Ritsert C. Jansen, Peter M. Visscher, Julian C. Knight, Bruce M. Psaty, Samuli Ripatti, Alexander Teumer, Timothy M. Frayling, Andres Metspalu, Joyce B. J. van Meurs, Lude Franke^*, Peter A.C. ’t Hoen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	1238-1243
Number of pages	6
Journal	Nature Genetics
Volume	45
Issue number	10
DOIs	https://doi.org/10.1038/ng.2756
Publication status	Published - Oct-2013

Keywords

GENOME-WIDE ASSOCIATION
GENE-EXPRESSION
LUPUS-ERYTHEMATOSUS
MYOCARDIAL-INFARCTION
SUSCEPTIBILITY LOCI
RISK
POPULATION
BLOOD
INTERFERON
VARIANTS

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Westra, H.-J., Peters, M. J., Esko, T., Yaghootkar, H., Schurmann, C., Kettunen, J., Christiansen, M. W., Fairfax, B. P., Schramm, K., Powell, J. E., Zhernakova, A., Zhernakova, D. V., Veldink, J. H., Van den Berg, L. H., Karjalainen, J., Withoff, S., Uitterlinden, A. G., Hofman, A., Rivadeneira, F., ... Hoen, P. A. C. . (2013). Systematic identification of trans eQTLs as putative drivers of known disease associations. Nature Genetics, 45(10), 1238-1243. https://doi.org/10.1038/ng.2756

@article{9be58926f59b4b9a9abc0296fe6595e4,

title = "Systematic identification of trans eQTLs as putative drivers of known disease associations",

abstract = "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.",

keywords = "GENOME-WIDE ASSOCIATION, GENE-EXPRESSION, LUPUS-ERYTHEMATOSUS, MYOCARDIAL-INFARCTION, SUSCEPTIBILITY LOCI, RISK, POPULATION, BLOOD, INTERFERON, VARIANTS",

author = "Harm-Jan Westra and Peters, \{Marjolein J.\} and Tonu Esko and Hanieh Yaghootkar and Claudia Schurmann and Johannes Kettunen and Christiansen, \{Mark W.\} and Fairfax, \{Benjamin P.\} and Katharina Schramm and Powell, \{Joseph E.\} and Alexandra Zhernakova and Zhernakova, \{Daria V.\} and Veldink, \{Jan H.\} and \{Van den Berg\}, \{Leonard H.\} and Juha Karjalainen and Sebo Withoff and Uitterlinden, \{Andre G.\} and Albert Hofman and Fernando Rivadeneira and \{'t Hoen\}, \{Peter A. C.\} and Eva Reinmaa and Krista Fischer and Mari Nelis and Lili Milani and David Melzer and Luigi Ferrucci and Singleton, \{Andrew B.\} and Hernandez, \{Dena G.\} and Nalls, \{Michael A.\} and Georg Homuth and Matthias Nauck and Doerte Radke and Uwe Voelker and Markus Perola and Veikko Salomaa and Jennifer Brody and Astrid Suchy-Dicey and Gharib, \{Sina A.\} and Enquobahrie, \{Daniel A.\} and Thomas Lumley and Montgomery, \{Grant W.\} and Seiko Makino and Holger Prokisch and Christian Herder and Michael Roden and Harald Grallert and Thomas Meitinger and Konstantin Strauch and Yang Li and Jansen, \{Ritsert C.\} and Visscher, \{Peter M.\} and Knight, \{Julian C.\} and Psaty, \{Bruce M.\} and Samuli Ripatti and Alexander Teumer and Frayling, \{Timothy M.\} and Andres Metspalu and \{van Meurs\}, \{Joyce B. J.\} and Lude Franke and Hoen, \{Peter A.C. {\textquoteright}t\}",

year = "2013",

month = oct,

doi = "10.1038/ng.2756",

language = "English",

volume = "45",

pages = "1238--1243",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

Westra, H-J, Peters, MJ, Esko, T, Yaghootkar, H, Schurmann, C, Kettunen, J, Christiansen, MW, Fairfax, BP, Schramm, K, Powell, JE, Zhernakova, A, Zhernakova, DV, Veldink, JH, Van den Berg, LH, Karjalainen, J, Withoff, S, Uitterlinden, AG, Hofman, A, Rivadeneira, F, 't Hoen, PAC, Reinmaa, E, Fischer, K, Nelis, M, Milani, L, Melzer, D, Ferrucci, L, Singleton, AB, Hernandez, DG, Nalls, MA, Homuth, G, Nauck, M, Radke, D, Voelker, U, Perola, M, Salomaa, V, Brody, J, Suchy-Dicey, A, Gharib, SA, Enquobahrie, DA, Lumley, T, Montgomery, GW, Makino, S, Prokisch, H, Herder, C, Roden, M, Grallert, H, Meitinger, T, Strauch, K, Li, Y, Jansen, RC, Visscher, PM, Knight, JC, Psaty, BM, Ripatti, S, Teumer, A, Frayling, TM, Metspalu, A, van Meurs, JBJ, Franke, L & Hoen, PAC 2013, 'Systematic identification of trans eQTLs as putative drivers of known disease associations', Nature Genetics, vol. 45, no. 10, pp. 1238-1243. https://doi.org/10.1038/ng.2756

TY - JOUR

T1 - Systematic identification of trans eQTLs as putative drivers of known disease associations

AU - Westra, Harm-Jan

AU - Peters, Marjolein J.

AU - Esko, Tonu

AU - Yaghootkar, Hanieh

AU - Schurmann, Claudia

AU - Kettunen, Johannes

AU - Christiansen, Mark W.

AU - Fairfax, Benjamin P.

AU - Schramm, Katharina

AU - Powell, Joseph E.

AU - Zhernakova, Alexandra

AU - Zhernakova, Daria V.

AU - Veldink, Jan H.

AU - Van den Berg, Leonard H.

AU - Karjalainen, Juha

AU - Withoff, Sebo

AU - Uitterlinden, Andre G.

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - 't Hoen, Peter A. C.

AU - Reinmaa, Eva

AU - Fischer, Krista

AU - Nelis, Mari

AU - Milani, Lili

AU - Melzer, David

AU - Ferrucci, Luigi

AU - Singleton, Andrew B.

AU - Hernandez, Dena G.

AU - Nalls, Michael A.

AU - Homuth, Georg

AU - Nauck, Matthias

AU - Radke, Doerte

AU - Voelker, Uwe

AU - Perola, Markus

AU - Salomaa, Veikko

AU - Brody, Jennifer

AU - Suchy-Dicey, Astrid

AU - Gharib, Sina A.

AU - Enquobahrie, Daniel A.

AU - Lumley, Thomas

AU - Montgomery, Grant W.

AU - Makino, Seiko

AU - Prokisch, Holger

AU - Herder, Christian

AU - Roden, Michael

AU - Grallert, Harald

AU - Meitinger, Thomas

AU - Strauch, Konstantin

AU - Li, Yang

AU - Jansen, Ritsert C.

AU - Visscher, Peter M.

AU - Knight, Julian C.

AU - Psaty, Bruce M.

AU - Ripatti, Samuli

AU - Teumer, Alexander

AU - Frayling, Timothy M.

AU - Metspalu, Andres

AU - van Meurs, Joyce B. J.

AU - Franke, Lude

AU - Hoen, Peter A.C. ’t

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - GENOME-WIDE ASSOCIATION

KW - GENE-EXPRESSION

KW - LUPUS-ERYTHEMATOSUS

KW - MYOCARDIAL-INFARCTION

KW - SUSCEPTIBILITY LOCI

KW - RISK

KW - POPULATION

KW - BLOOD

KW - INTERFERON

KW - VARIANTS

U2 - 10.1038/ng.2756

DO - 10.1038/ng.2756

M3 - Article

SN - 1061-4036

VL - 45

SP - 1238

EP - 1243

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

Abstract

Keywords

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