title: Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.
abstract: OBJECTIVE
  To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS).
  
  
  METHODS
  Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research.
  
  
  METHODS
  Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012).
  
  
  METHODS
  A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P < 8.3 × 10(-3)). RLS symptoms were categorized into four groups: likely, possible, no symptoms, and unknown based on a mailed survey response.
  
  
  RESULTS
  Prevalence of PLMI ≥ 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI > 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations.
  
  
  CONCLUSIONS
  Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.
authors.forename: Hyatt
authors.initials: H
authors.lastname: Moore
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Laurel
authors.initials: L
authors.lastname: Finn
authors.forename: Paul
authors.initials: P
authors.lastname: Peppard
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
mesh_terms: D051017:Apoptosis Regulatory Proteins; D015331:Cohort Studies; D005260:Female; D006609:High Mobility Group Proteins; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins; D020189:Nocturnal Myoclonus Syndrome / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D012148:Restless Legs Syndrome / Q000453:epidemiology / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D014922:Wisconsin / Q000453:epidemiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C522207:BTBD9 protein, human; D006609:High Mobility Group Proteins; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011980:Receptors, Progesterone; C521752:TOX3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: Wisconsin Sleep Cohort; genetics; periodic leg movements; polysomnography; restless legs syndrome