title: Blood cis-eQTL analysis fails to identify novel association signals among sub-threshold candidates from genome-wide association studies in restless legs syndrome.
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.
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Schulte
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schramm
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.affiliation: Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), partner Düsseldorf, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), partner Düsseldorf, Düsseldorf, Germany; University Clinics of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: Institute for Genetic Epidemiology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Institute for Epidemiology II, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Paracelsus Elena Klinik, Kassel, Germany; Department of Neurosurgery, University Medical Center, Georg August Universität Göttingen, Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Trenkwalder
authors.affiliation: Neurologische Klinik, Medizinische Universität Innsbruck, Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Högl
authors.affiliation: Neurologische Klinik, Medizinische Universität Innsbruck, Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Frauscher
authors.affiliation: Institut für Epidemiologie und Sozialmedizin, Westfälische Wilhelms Universität Münster, Münster, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Berger
authors.affiliation: Zentrum für Schlafmedizin, Charite Universitätsmedizin, Berlin, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Fietze
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Gross
authors.affiliation: Neurologische Klinik, Philips Universität Marburg, Marburg, Germany; Somnomar Institut für Medizinische Forschung und Schlafmedizin, Marburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Stiasny-Kolster
authors.affiliation: Neurologische Klinik, Philips Universität Marburg, Marburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Oertel
authors.affiliation: Abteilung für Neurologie, Paracelsus Klinik Osnabrück, Osnabrück, Germany.
authors.forename: Cornelius G
authors.initials: CG
authors.lastname: Bachmann
authors.affiliation: Department of Clinical Neurophysiology, University Medical Center, Georg August Universität Göttingen, Göttingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Paulus
authors.affiliation: Neurologische Klinik, Medizinische Universität Wien, Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimprich
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Institute of Neurology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schminke
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany; Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Max-Planck Institute for Psychiatry, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012045:Regulatory Sequences, Nucleic Acid; D012148:Restless Legs Syndrome / Q000235:genetics*; D055815:Young Adult