title: A genetic risk factor for periodic limb movements in sleep.
abstract: BACKGROUND
  The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric.
  
  
  METHODS
  To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS.
  
  
  RESULTS
  In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002).
  
  
  CONCLUSIONS
  We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.
authors.affiliation: deCODE Genetics, Reykjavik, Iceland. kstefans@decode.is
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: David B
authors.initials: DB
authors.lastname: Rye
authors.forename: Andrew
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authors.lastname: Hicks
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authors.initials: TE
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authors.lastname: Palsson
authors.forename: Thordur
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authors.lastname: Sigmundsson
authors.forename: Albert P
authors.initials: AP
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authors.forename: Ingibjorg
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authors.lastname: Eiriksdottir
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authors.lastname: Soebech
authors.forename: Donald
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authors.lastname: Bliwise
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authors.initials: JM
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authors.forename: Ami
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authors.initials: LM
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authors.forename: Madhav
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authors.lastname: Thambisetty
authors.forename: Gudmundur A
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authors.lastname: Hardarson
authors.forename: Kristleifur
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authors.lastname: Kristjansson
authors.forename: Larus J
authors.initials: LJ
authors.lastname: Gudmundsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Augustine
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authors.lastname: Kong
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gulcher
authors.forename: Daniel
authors.initials: D
authors.lastname: Gudbjartsson
authors.forename: Kari
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authors.lastname: Stefansson
mesh_terms: D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6; D005260:Female; D005293:Ferritins / Q000097:blood; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D000090463:Iron Deficiencies; D015810:Linkage Disequilibrium; D008297:Male; D009419:Nerve Tissue Proteins; D020189:Nocturnal Myoclonus Syndrome / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012148:Restless Legs Syndrome / Q000097:blood / Q000235:genetics*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C522207:BTBD9 protein, human; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D005293:Ferritins