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. 2014 May 29;9(5):e98092.
doi: 10.1371/journal.pone.0098092. eCollection 2014.

Blood cis-eQTL Analysis Fails to Identify Novel Association Signals Among Sub-Threshold Candidates From Genome-Wide Association Studies in Restless Legs Syndrome

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Blood cis-eQTL Analysis Fails to Identify Novel Association Signals Among Sub-Threshold Candidates From Genome-Wide Association Studies in Restless Legs Syndrome

Eva C Schulte et al. PLoS One. .
Free PMC article

Abstract

Restless legs syndrome (RLS) is a common neurologic disorder characterized by nightly dysesthesias affecting the legs primarily during periods of rest and relieved by movement. RLS is a complex genetic disease and susceptibility factors in six genomic regions have been identified by means of genome-wide association studies (GWAS). For some complex genetic traits, expression quantitative trait loci (eQTLs) are enriched among trait-associated single nucleotide polymorphisms (SNPs). With the aim of identifying new genetic susceptibility factors for RLS, we assessed the 332 best-associated SNPs from the genome-wide phase of the to date largest RLS GWAS for cis-eQTL effects in peripheral blood from individuals of European descent. In 740 individuals belonging to the KORA general population cohort, 52 cis-eQTLs with pnominal<10(-3) were identified, while in 976 individuals belonging to the SHIP-TREND general population study 53 cis-eQTLs with pnominal<10(-3) were present. 23 of these cis-eQTLs overlapped between the two cohorts. Subsequently, the twelve of the 23 cis-eQTL SNPs, which were not located at an already published RLS-associated locus, were tested for association in 2449 RLS cases and 1462 controls. The top SNP, located in the DET1 gene, was nominally significant (p<0.05) but did not withstand correction for multiple testing (p = 0.42). Although a similar approach has been used successfully with regard to other complex diseases, we were unable to identify new genetic susceptibility factor for RLS by adding this novel level of functional assessment to RLS GWAS data.

Conflict of interest statement

Competing Interests: Parts of this study were funded by commercial sources (InterSystems GmbH and Siemens Healthcare). Also, Christian Herder is an academic editor for PLoS ONE. These do not alter the authors’ adherence to PLoS ONE Editorial policies and criteria.

Figures

Figure 1
Figure 1. Study Design.

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Grant support

Recruitment of the KORA cohort was supported by institutional (Helmholtz Zentrum München, Munich, Germany) and government funding from the German Bundesministerium für Bildung und Forschung (03.2007-02.2011 FKZ 01ET0713). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Deutsche Forschungsgemeinschaft (DFG GRK840-D2), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. This work is also part of the research project Greifswald Approach to Individualized Medicine (GANI_MED), which is funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg–West Pomerania (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg, West Pomerania. Whole-body MR imaging was supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG and the Caché Campus program of the InterSystems GmbH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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