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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), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. 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.

SUBMITTER: Westra HJ 

PROVIDER: S-EPMC3991562 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Westra Harm-Jan HJ   Peters Marjolein J MJ   Esko Tõnu T   Yaghootkar Hanieh H   Schurmann Claudia C   Kettunen Johannes J   Christiansen Mark W MW   Fairfax Benjamin P BP   Schramm Katharina K   Powell Joseph E JE   Zhernakova Alexandra A   Zhernakova Daria V DV   Veldink Jan H JH   Van den Berg Leonard H LH   Karjalainen Juha J   Withoff Sebo S   Uitterlinden André G AG   Hofman Albert A   Rivadeneira Fernando F   Hoen Peter A C 't PAC'   Reinmaa Eva E   Fischer Krista K   Nelis Mari M   Milani Lili L   Melzer David D   Ferrucci Luigi L   Singleton Andrew B AB   Hernandez Dena G DG   Nalls Michael A MA   Homuth Georg G   Nauck Matthias M   Radke Dörte D   Völker Uwe U   Perola Markus M   Salomaa Veikko V   Brody Jennifer J   Suchy-Dicey Astrid A   Gharib Sina A SA   Enquobahrie Daniel A DA   Lumley Thomas T   Montgomery Grant W GW   Makino Seiko S   Prokisch Holger H   Herder Christian C   Roden Michael M   Grallert Harald H   Meitinger Thomas T   Strauch Konstantin K   Li Yang Y   Jansen Ritsert C RC   Visscher Peter M PM   Knight Julian C JC   Psaty Bruce M BM   Ripatti Samuli S   Teumer Alexander A   Frayling Timothy M TM   Metspalu Andres A   van Meurs Joyce B J JBJ   Franke Lude L  

Nature genetics 20130908 10


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 tr  ...[more]

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