title: Analysis of functional GLO1 variants in the BTBD9 locus and restless legs syndrome.
abstract: BACKGROUND
  Restless legs syndrome (RLS) is a common disorder, with several known genetic risk factors, yet the actual genetic causes are unclear.
  
  
  METHODS
  Whole-exome sequencing (WES) was performed in seven RLS families, focusing on six known genetic loci: MEIS1, BTBD9, PTPRD, MAP2K5/SKOR1, TOX3, and rs6747972. Genotyping using specific TaqMan assays was performed in two case-control cohorts (627 patients and 410 controls), and in a familial cohort (n = 718).
  
  
  RESULTS
  WES identified two candidate GLO1 variants (within the BTBD9 locus), p.E111A and the promoter variant c.-7C>T, both co-segregated with the disease in four families. The GLO1 p.E111A variant was associated with RLS in the French-Canadian cohort (odds ratio, OR = 1.38, p = 0.02), and demonstrated a similar trend in the US cohort (OR = 1.26, p = 0.09, combined analysis OR = 1.28, p = 0.009). However, the original genome-wide association study (GWAS) marker, BTBD9 rs9357271, had stronger association with RLS (OR = 1.84, p = 0.0003). Conditional haplotype analysis, controlling for the effect of the BTBD9 variant rs9357271, demonstrated that the association of GLO1 p.E111A turned insignificant (p = 0.54). In the familial cohort, the two GLO1 variants were not associated with RLS. Other variants in the SKOR1 (p.W200R and p.A672V) and PTPRD (p.R995C, p.Q447E, p.T781A, p.Q447E, and c.551-4C > G) genes, did not co-segregate with the disease.
  
  
  CONCLUSIONS
  The GLO1 variations studied here are not the source of association of the BTBD9 locus with RLS. It is likely that the genetic variants affecting RLS susceptibility are located in regulatory regions.
authors: Montreal Neurological Institute and McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada.
authors: Ziv
authors: Z
authors: Gan-Or
authors: Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors: Sirui
authors: S
authors: Zhou
authors: Montreal Neurological Institute and McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada.
authors: Amirthagowri
authors: A
authors: Ambalavanan
authors: Montreal Neurological Institute and McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada.
authors: Claire S
authors: CS
authors: Leblond
authors: Montreal Neurological Institute and McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada.
authors: Pingxing
authors: P
authors: Xie
authors: Laboratory of Neurogenetics, Research Centre, Montreal Mental Health University Institute, Montréal, QC, Canada.
authors: Amelie
authors: A
authors: Johnson
authors: Montreal Neurological Institute and McGill University, Montréal, QC, Canada.
authors: Dan
authors: D
authors: Spiegelman
authors: Department of Neurology, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.
authors: Richard P
authors: RP
authors: Allen
authors: Department of Neurology, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.
authors: Christopher J
authors: CJ
authors: Earley
authors: Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, Canada; Department of Neurosciences, Université de Montréal, Montréal, QC, Canada.
authors: Alex
authors: A
authors: Desautels
authors: Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, Canada; Department of Psychiatry, Université de Montréal, Montréal, QC, Canada.
authors: Jacques Y
authors: JY
authors: Montplaisir
authors: Montreal Neurological Institute and McGill University, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
authors: Patrick A
authors: PA
authors: Dion
authors: Laboratory of Neurogenetics, Research Centre, Montreal Mental Health University Institute, Montréal, QC, Canada; Department of Psychiatry, Université de Montréal, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
authors: Lan
authors: L
authors: Xiong
authors: Montreal Neurological Institute and McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada. Electronic address: guy.rouleau@mcgill.ca.
authors: Guy A
authors: GA
authors: Rouleau
mesh_terms: D000328:Adult; D002170:Canada; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins; D010375:Pedigree; D012148:Restless Legs Syndrome / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014481:United States
chemical_list: C522207:BTBD9 protein, human; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C000597196:GLO1 protein, human; D007791:Lactoylglutathione Lyase
keywords: BTBD9; GLO1; Genetics; RLS; Restless legs syndrome