Analysis of functional GLO1 variants in the BTBD9 locus and restless legs syndrome

Ziv Gan-Or; Sirui Zhou; Amirthagowri Ambalavanan; Claire S Leblond; Pingxing Xie; Amelie Johnson; Dan Spiegelman; Richard P Allen; Christopher J Earley; Alex Desautels; Jacques Y Montplaisir; Patrick A Dion; Lan Xiong; Guy A Rouleau

doi:10.1016/j.sleep.2015.06.002

Analysis of functional GLO1 variants in the BTBD9 locus and restless legs syndrome

Sleep Med. 2015 Sep;16(9):1151-5. doi: 10.1016/j.sleep.2015.06.002. Epub 2015 Jun 17.

Authors

Affiliations

¹ Montreal Neurological Institute and McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada.
² Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
³ Laboratory of Neurogenetics, Research Centre, Montreal Mental Health University Institute, Montréal, QC, Canada.
⁴ Montreal Neurological Institute and McGill University, Montréal, QC, Canada.
⁵ Department of Neurology, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.
⁶ 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.
⁷ 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.
⁸ Montreal Neurological Institute and McGill University, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
⁹ 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.
¹⁰ 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: [email protected].

PMID: 26298793
DOI: 10.1016/j.sleep.2015.06.002

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.

Keywords: BTBD9; GLO1; Genetics; RLS; Restless legs syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Canada
Case-Control Studies
Cohort Studies
Female
Genome-Wide Association Study
Humans
Lactoylglutathione Lyase / genetics*
Male
Nerve Tissue Proteins
Pedigree
Restless Legs Syndrome / genetics*
Transcription Factors / genetics*
United States

Substances

BTBD9 protein, human
Nerve Tissue Proteins
Transcription Factors
GLO1 protein, human
Lactoylglutathione Lyase

Grants and funding

MOP-82900/Canadian Institutes of Health Research/Canada