RT Journal
A1 Spieler, Derek
A1 Kaffe, Maria
A1 Knauf, Franziska
A1 Bessa, José
A1 Tena, Juan J.
A1 Giesert, Florian
A1 Schormair, Barbara
A1 Tilch, Erik
A1 Lee, Heekyoung
A1 Horsch, Marion
A1 Czamara, Darina
A1 Karbalai, Nazanin
A1 von Toerne, Christine
A1 Waldenberger, Melanie
A1 Gieger, Christian
A1 Lichtner, Peter
A1 Claussnitzer, Melina
A1 Naumann, Ronald
A1 Müller-Myhsok, Bertram
A1 Torres, Miguel
A1 Garrett, Lillian
A1 Rozman, Jan
A1 Klingenspor, Martin
A1 Gailus-Durner, Valérie
A1 Fuchs, Helmut
A1 Hrabě de Angelis, Martin
A1 Beckers, Johannes
A1 Hölter, Sabine M.
A1 Meitinger, Thomas
A1 Hauck, Stefanie M.
A1 Laumen, Helmut
A1 Wurst, Wolfgang
A1 Casares, Fernando
A1 Gómez-Skarmeta, Jose Luis
A1 Winkelmann, Juliane
T1 Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon
JF Genome Research 
JO Genome Research 
YR 2014 
FD April 01 
VO 24 
IS 4 
SP 592 
OP 603 
DO 10.1101/gr.166751.113 
UL http://genome.cshlp.org/content/24/4/592.abstract 
AB Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.