A direct interaction between two Restless Legs Syndrome predisposing genes: MEIS1 and SKOR1

Sci Rep. 2018 Aug 15;8(1):12173. doi: 10.1038/s41598-018-30665-6.


Restless Legs syndrome (RLS) is a common sleep disorder for which the genetic contribution remains poorly explained. In 2007, the first large scale genome wide association study (GWAS) identified three genomic regions associated with RLS. MEIS1, BTBD9 and MAP2K5/SKOR1 are the only known genes located within these loci and their association with RLS was subsequently confirmed in a number of follow up GWAS. Following this finding, our group reported the MEIS1 risk haplotype to be associated with its decreased expression at the mRNA and protein levels. Here we report the effect of the risk variants of the three other genes strongly associated with RLS. While these variants had no effect on the mRNA levels of the genes harboring them, we find that the homeobox transcription factor MEIS1 positively regulates the expression of the transcription co-repressor SKOR1. This regulation appears mediated through the binding of MEIS1 at two specific sites located in the SKOR1 promoter region and is modified by an RLS associated SNP in the promoter region of the gene. Our findings directly link MEIS1 and SKOR1, two significantly associated genes with RLS and also prioritize SKOR1 over MAP2K5 in the RLS associated intergenic region of MAP2K5/SKOR1 found by GWAS.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Co-Repressor Proteins / genetics*
  • Co-Repressor Proteins / metabolism
  • Female
  • Genes, Homeobox / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Haplotypes
  • Homeodomain Proteins / genetics
  • Humans
  • MAP Kinase Kinase 5 / genetics
  • MAP Kinase Kinase 5 / metabolism
  • Male
  • Middle Aged
  • Myeloid Ecotropic Viral Integration Site 1 Protein / genetics*
  • Myeloid Ecotropic Viral Integration Site 1 Protein / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Restless Legs Syndrome / genetics*
  • Transcription Factors / genetics


  • Co-Repressor Proteins
  • Homeodomain Proteins
  • MEIS1 protein, human
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • SKOR1 protein, human
  • Transcription Factors
  • MAP Kinase Kinase 5
  • MAP2K5 protein, human