Genetics of restless legs syndrome.
Restless legs syndrome (RLS) is a highly familial trait with heritability estimates of about 50%. It is a polygenetic disorder in which a number of variants contribute to the phenotype. Linkage studies in families with RLS revealed several loci but have not yet led to the identification of disease-causing sequence variants. Phenocopies, nonpenetrance, and possible intrafamilial heterogeneity make it difficult to define the exact candidate region. Genome-wide association studies identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/LBOXCOR1. Carriers of one risk allele had a 50% increased risk of developing RLS. MEIS1 and LBXCOR1 are developmental factors and raise new pathophysiologic questions for RLS. These variants have weak and moderate effects and increase the risk of developing RLS. It is still possible that strong effects explain the occurrence of RLS in families. Therefore, linkage and association studies should be used congruently to dissect the complete genetic architecture of RLS.
Winkelmann
Juliane
J
Helmholz Center Munich, National Research Center for Environment and Health, Munich Institute of Human Genetics, Ingolstaedter Landstrasse 1, D-85764 Munich-Neuherberg, Germany. julianewinkelmann@t-online.de
D005192:Family Health; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000235:genetics; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins; D012148:Restless Legs Syndrome / Q000235:genetics* / Q000503:physiopathology; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics
C522207:BTBD9 protein, human; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human