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Parkinsonism Relat Disord. 2018 Jul;52:98-101. doi: 10.1016/j.parkreldis.2018.03.019. Epub 2018 Mar 21.

LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder.

Author information

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.

KEYWORDS:

Genetics; LRRK2; Parkinson disease; REM sleep behavior disorder

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