Bouchra Ouled Amar Bencheikh1, Jennifer A Ruskey2, Isabelle Arnulf3, Yves Dauvilliers4, Christelle Charley Monaca5, Valérie Cochen De Cock6, Jean-François Gagnon7, Dan Spiegelman2, Michele T M Hu8, Birgit Högl9, Ambra Stefani9, Luigi Ferini-Strambi10, Giuseppe Plazzi11, Elena Antelmi11, Peter Young12, Anna Heidbreder12, Brit Mollenhauer13, Friederike Sixel-Döring14, Claudia Trenkwalder13, Wolfgang Oertel15, Jacques Y Montplaisir16, Ronald B Postuma17, Guy A Rouleau18, Ziv Gan-Or19. 1. Montreal Neurological Institute, McGill University, Montréal, QC, H3A 0G4, Canada; Centre de Recherche, Centre Hospitalier de l'Universite de Montreal, Montreal, QC H2X 0A9, Canada. 2. Montreal Neurological Institute, McGill University, Montréal, QC, H3A 0G4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, H3A 0G4, Canada, Canada. 3. Sleep Disorders Unit, Pitié Salpêtrière Hospital, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière and Sorbonne Universities, UPMC Paris 6 Univ, Paris, 75013, France. 4. Sleep Unit, National Reference Network for Narcolepsy, Department of Neurology Hôpital-Gui-de Chauliac, CHU Montpellier, INSERM U1061, Montpellier, 34000, France. 5. University Lille North of France, Department of Clinical Neurophysiology and Sleep Center, CHU Lille, Lille, 59000, France. 6. Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, 34070, France; EuroMov, University of Montpellier, Montpellier, 34095, France. 7. Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, H4J 1C5, Canada; Département de Psychologie, Université du Québec à Montréal, Montréal, QC, H2L 2C4, Canada. 8. Oxford Parkinson's Disease Centre (OPDC), University of Oxford, Oxford, OX1 2JD, United Kingdom; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX1 2JD, United Kingdom. 9. Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, 6020, Austria. 10. Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, 20132, Italy. 11. Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, 40126, Italy; IRCCS, Institute of Neurological Sciences of Bologna, Bologna, 40139, Italy. 12. Department of Sleep Medicine and Neuromuscular Disorders, University of Muenster, 48149, Germany. 13. Paracelsus-Elena Clinic, Centre of Parkinsonism and Movement Disorders, Kassel, Germany. 14. Paracelsus-Elena Clinic, Centre of Parkinsonism and Movement Disorders, Kassel, Germany; University Medical Center Goettingen, Department of Neurology, 37075 Goettingen, Germany. 15. Department of Neurology, University Clinic, Philipps Universität Marburg, Marburg, Germany; Institute for Neurogenomics, Helmholtz Center for Health and Environment, Munich, Germany. 16. Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, H4J 1C5, Canada; Department of Psychiatry, Université de Montréal, Montréal, QC, H3T 1J4, Canada. 17. Montreal Neurological Institute, McGill University, Montréal, QC, H3A 0G4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, H3A 0G4, Canada, Canada; Department of Neurology, Montreal General Hospital, Montréal, QC, H3G 1A4, Canada. 18. Montreal Neurological Institute, McGill University, Montréal, QC, H3A 0G4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, H3A 0G4, Canada, Canada; Department of Human Genetics, McGill University, H3A 0G4, Montréal, QC, Canada. 19. Montreal Neurological Institute, McGill University, Montréal, QC, H3A 0G4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, H3A 0G4, Canada, Canada; Department of Human Genetics, McGill University, H3A 0G4, Montréal, QC, Canada. Electronic address: ziv.gan-or@mcgill.ca.
Abstract
BACKGROUND: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear. METHODS: The full coding sequence, exon-intron boundaries and 5' and 3' untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD. RESULTS: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44-0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05-1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified. CONCLUSIONS: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD.
BACKGROUND: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear. METHODS: The full coding sequence, exon-intron boundaries and 5' and 3' untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD. RESULTS: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44-0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05-1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified. CONCLUSIONS: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD.
Authors: Mitchell G Miglis; Charles H Adler; Elena Antelmi; Dario Arnaldi; Luca Baldelli; Bradley F Boeve; Matteo Cesari; Irene Dall'Antonia; Nico J Diederich; Kathrin Doppler; Petr Dušek; Raffaele Ferri; Jean-François Gagnon; Ziv Gan-Or; Wiebke Hermann; Birgit Högl; Michele T Hu; Alex Iranzo; Annette Janzen; Anastasia Kuzkina; Jee-Young Lee; Klaus L Leenders; Simon J G Lewis; Claudio Liguori; Jun Liu; Christine Lo; Kaylena A Ehgoetz Martens; Jiri Nepozitek; Giuseppe Plazzi; Federica Provini; Monica Puligheddu; Michal Rolinski; Jan Rusz; Ambra Stefani; Rebekah L S Summers; Dallah Yoo; Jennifer Zitser; Wolfgang H Oertel Journal: Lancet Neurol Date: 2021-08 Impact factor: 44.182
Authors: Lynne Krohn; Richard Y J Wu; Karl Heilbron; Jennifer A Ruskey; Sandra B Laurent; Cornelis Blauwendraat; Armaghan Alam; Isabelle Arnulf; Michele T M Hu; Yves Dauvilliers; Birgit Högl; Mathias Toft; Kari Anne Bjørnarå; Ambra Stefani; Evi Holzknecht; Christelle Charley Monaca; Beatriz Abril; Giuseppe Plazzi; Elena Antelmi; Luigi Ferini-Strambi; Peter Young; Anna Heidbreder; Valérie Cochen De Cock; Brit Mollenhauer; Friederike Sixel-Döring; Claudia Trenkwalder; Karel Sonka; David Kemlink; Michela Figorilli; Monica Puligheddu; Femke Dijkstra; Mineke Viaene; Wolfang Oertel; Marco Toffoli; Gian Luigi Gigli; Mariarosaria Valente; Jean-François Gagnon; Mike A Nalls; Andrew B Singleton; Alex Desautels; Jacques Y Montplaisir; Paul Cannon; Owen A Ross; Bradley F Boeve; Nicolas Dupré; Edward A Fon; Ronald B Postuma; Lasse Pihlstrøm; Guy A Rouleau; Ziv Gan-Or Journal: Ann Neurol Date: 2020-02-12 Impact factor: 11.274
Authors: Ziv Gan-Or; Trisha Rao; Etienne Leveille; Clotilde Degroot; Sylvain Chouinard; Francesca Cicchetti; Alain Dagher; Samir Das; Alex Desautels; Janelle Drouin-Ouellet; Thomas Durcan; Jean-François Gagnon; Angela Genge; Jason Karamchandani; Anne-Louise Lafontaine; Sonia Lai Wing Sun; Mélanie Langlois; Martin Levesque; Calvin Melmed; Michel Panisset; Martin Parent; Jean-Baptiste Poline; Ronald B Postuma; Emmanuelle Pourcher; Guy A Rouleau; Madeleine Sharp; Oury Monchi; Nicolas Dupré; Edward A Fon Journal: J Parkinsons Dis Date: 2020 Impact factor: 5.568
Authors: Kheireddin Mufti; Eric Yu; Uladzislau Rudakou; Lynne Krohn; Jennifer A Ruskey; Farnaz Asayesh; Sandra B Laurent; Dan Spiegelman; Isabelle Arnulf; Michele T M Hu; Jacques Y Montplaisir; Jean-François Gagnon; Alex Desautels; Yves Dauvilliers; Gian Luigi Gigli; Mariarosaria Valente; Francesco Janes; Andrea Bernardini; Birgit Högl; Ambra Stefani; Evi Holzknecht; Karel Sonka; David Kemlink; Wolfgang Oertel; Annette Janzen; Giuseppe Plazzi; Elena Antelmi; Michela Figorilli; Monica Puligheddu; Brit Mollenhauer; Claudia Trenkwalder; Friederike Sixel-Döring; Valérie Cochen De Cock; Christelle Charley Monaca; Anna Heidbreder; Luigi Ferini-Strambi; Femke Dijkstra; Mineke Viaene; Beatriz Abril; Bradley F Boeve; Jean-François Trempe; Guy A Rouleau; Ronald B Postuma; Ziv Gan-Or Journal: Neurology Date: 2021-01-04 Impact factor: 9.910