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Ann Neurol. 2020 Apr;87(4):584-598. doi: 10.1002/ana.25687. Epub 2020 Feb 12.

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

Author information

1
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
2
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
3
Department of Medicine, Imperial College London, London, United Kingdom.
4
23andMe, Mountain View, CA.
5
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
6
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD.
7
Sleep Disorders Unit, Pitié-Salpêtrière Hospital, Institute for Brain and Spinal Cord, and Sorbonne University, Paris, France.
8
Oxford Parkinson's Disease Center, University of Oxford, Oxford, United Kingdom.
9
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
10
National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui de Chauliac Hospital, University Hospital of Montpellier, University of Montpellier, Montpellier, France.
11
Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
12
Department of Neurology, Oslo University Hospital, Oslo, Norway.
13
Institue of Clinical Medicine, University of Oslo, Oslo, Norway.
14
Department of Clinical Neurophysiology and Sleep Center, University Hospital of Lille, University of Lille North of France, Lille, France.
15
Sleep Disorder Unit, Carémeau Hospital, University Hospital of Nîmes, Nîmes, France.
16
Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
17
Institute of Neurological Sciences, Scientific Institute for Research and Health Care, Bologna, Italy.
18
Department of Neurological Sciences, Vita-Salute San Raffaele University, Milan, Italy.
19
Department of Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany.
20
Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France.
21
EuroMov, University of Montpellier, Montpellier, France.
22
Paracelsus Elena Clinic, Kassel, Germany.
23
Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.
24
Department of Neurology and Center of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
25
Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
26
Laboratory for Sleep Disorders, St Dimpna Regional Hospital, Geel, Belgium.
27
Department of Neurology, St Dimpna Regional Hospital, Geel, Belgium.
28
Department of Neurology, Philipps University, Marburg, Germany.
29
Department of Medicine, University of Udine, Udine, Italy.
30
Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK.
31
Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.
32
Department of Mathematics, Informatics, and Physics, University of Udine, Udine, Italy.
33
Center for Advanced Studies in Sleep Medicine, Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
34
Department of Psychology, Université du Québec à Montréal, Montréal, QC, Canada.
35
Data Tecnica International, Glen Echo, MD.
36
Department of Neurosciences, University of Montreal, Montreal, Quebec, Canada.
37
Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada.
38
Departments of Neuroscience and Clinical Genomics, Mayo Clinic, Jacksonville, FL.
39
Department of Neurology, Mayo Clinic, Rochester, MN.
40
Division of Neurosciences, University Hospital of Quebec, Laval University, Quebec City, Quebec, Canada.
41
Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.

Abstract

OBJECTIVE:

Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.

METHODS:

Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.

RESULTS:

A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD.

INTERPRETATION:

There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.

PMID:
31976583
DOI:
10.1002/ana.25687

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