Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions.
Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.
Winkelmann
Juliane
J
Institute of Human Genetics, GSF National Research Center of Environment and Health, D-85764 Neuherberg, Munich, Germany. janew@mpipsykl.mpg.de
Schormair
Barbara
B
Lichtner
Peter
P
Ripke
Stephan
S
Xiong
Lan
L
Jalilzadeh
Shapour
S
Fulda
Stephany
S
Pütz
Benno
B
Eckstein
Gertrud
G
Hauk
Stephanie
S
Trenkwalder
Claudia
C
Zimprich
Alexander
A
Stiasny-Kolster
Karin
K
Oertel
Wolfgang
W
Bachmann
Cornelius G
CG
Paulus
Walter
W
Peglau
Ines
I
Eisensehr
Ilonka
I
Montplaisir
Jacques
J
Turecki
Gustavo
G
Rouleau
Guy
G
Gieger
Christian
C
Illig
Thomas
T
Wichmann
H-Erich
HE
Holsboer
Florian
F
Müller-Myhsok
Bertram
B
Meitinger
Thomas
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D002889:Chromosomes, Human, Pair 2; D002896:Chromosomes, Human, Pair 6; D056970:Co-Repressor Proteins; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007438:Introns; D048671:MAP Kinase Kinase 5 / Q000235:genetics; D008875:Middle Aged; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics; D012148:Restless Legs Syndrome / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics
C522207:BTBD9 protein, human; D056970:Co-Repressor Proteins; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; C522810:SKOR1 protein, human; D014157:Transcription Factors; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human