Ziv Gan-Or1, Sirui Zhou2, Amirthagowri Ambalavanan1, Claire S Leblond1, Pingxing Xie1, Amelie Johnson3, Dan Spiegelman4, Richard P Allen5, Christopher J Earley5, Alex Desautels6, Jacques Y Montplaisir7, Patrick A Dion8, Lan Xiong9, Guy A Rouleau10. 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: guy.rouleau@mcgill.ca.
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.
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 GLO1p.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, BTBD9rs9357271, 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 GLO1p.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: Sadaf Mohtashami; Qin He; Jennifer A Ruskey; Sirui Zhou; Patrick A Dion; Richard P Allen; Christopher J Earley; Edward A Fon; Lan Xiong; Nicolas Dupre; Yves Dauvilliers; Guy A Rouleau; Ziv Gan-Or Journal: J Mol Neurosci Date: 2018-02-05 Impact factor: 3.444
Authors: Wejdan M Alenezi; Larissa Milano; Caitlin T Fierheller; Corinne Serruya; Timothée Revil; Kathleen K Oros; Supriya Behl; Suzanna L Arcand; Porangana Nayar; Dan Spiegelman; Simon Gravel; Anne-Marie Mes-Masson; Diane Provencher; William D Foulkes; Zaki El Haffaf; Guy Rouleau; Luigi Bouchard; Celia M T Greenwood; Jean-Yves Masson; Jiannis Ragoussis; Patricia N Tonin Journal: Cancers (Basel) Date: 2022-04-30 Impact factor: 6.575
Authors: Helene Catoire; Faezeh Sarayloo; Karim Mourabit Amari; Sergio Apuzzo; Alanna Grant; Daniel Rochefort; Lan Xiong; Jacques Montplaisir; Christopher J Earley; Gustavo Turecki; Patrick A Dion; Guy A Rouleau Journal: Sci Rep Date: 2018-08-15 Impact factor: 4.379
Authors: Ziv Gan-Or; Sirui Zhou; Amelie Johnson; Jacques Y Montplaisir; Richard P Allen; Christopher J Earley; Alex Desautels; Patrick A Dion; Lan Xiong; Guy A Rouleau Journal: Mov Disord Clin Pract Date: 2016-01-09