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

Abstract

Restless Legs syndrome (RLS) is a common sleep disorder for which the genetic contribution remains poorly explained. In 2007, the frst large scale genome wide association study (GWAS) identifed 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 confrmed in a number of follow up GWAS. Following this fnding, our group reported the MEIS1 risk haplotype to be associated with its decreased expression at the mRNA and protein levels. Here we report the efect of the risk variants of the three other genes strongly associated with RLS. While these variants had no efect on the mRNA levels of the genes harboring them, we fnd 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 specifc sites located in the SKOR1 promoter region and is modifed by an RLS associated SNP in the promoter region of the gene. Our fndings directly link MEIS1 and SKOR1, two signifcantly associated genes with RLS and also prioritize SKOR1 over MAP2K5 in the RLS associated intergenic region of MAP2K5/SKOR1 found by GWAS.