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.

Center for Advanced Studies in Sleep Medicine Centre d'Études Avancées en Médecine du Sommeil Hôpital du Sacré Coeur de Montréal Montreal Quebec Canada

Clinical Neurology Unit Department of Neurosciences University Hospital of Udine Udine Italy

Data Tecnica International Glen Echo MD

Department of Biomedical and Neuromotor Sciences Alma Mater Studiorum University of Bologna Bologna Italy

Department of Clinical and Movement Neurosciences University College London Queen Square Institute of Neurology London UK

Department of Clinical Neurophysiology and Sleep Center University Hospital of Lille University of Lille North of France Lille France

Department of Human Genetics McGill University Montreal Quebec Canada

Department of Mathematics Informatics and Physics University of Udine Udine Italy

Department of Medical Sciences and Public Health Sleep Disorder Research Center University of Cagliari Cagliari Italy

Department of Medicine Faculty of Medicine Laval University Quebec City Quebec Canada

Department of Medicine Imperial College London London United Kingdom

Department of Medicine University of Udine Udine Italy

Department of Neurological Sciences Vita Salute San Raffaele University Milan Italy

Department of Neurology and Center of Clinical Neuroscience Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Neurology and Neurosurgery McGill University Montreal Quebec Canada

Department of Neurology Mayo Clinic Rochester MN

Department of Neurology Oslo University Hospital Oslo Norway

Department of Neurology Philipps University Marburg Germany

Department of Neurology St Dimpna Regional Hospital Geel Belgium

Department of Neurosciences University of Montreal Montreal Quebec Canada

Department of Neurosurgery University Medical Center Göttingen Göttingen Germany

Department of Psychiatry University of Montreal Montreal Quebec Canada

Department of Psychology Université du Québec à Montréal Montréal QC Canada

Department of Sleep Medicine and Neuromuscular Disorders University of Münster Münster Germany

Departments of Neuroscience and Clinical Genomics Mayo Clinic Jacksonville FL

Division of Neurosciences University Hospital of Quebec Laval University Quebec City Quebec Canada

EuroMov University of Montpellier Montpellier France

Institue of Clinical Medicine University of Oslo Oslo Norway

Institute of Neurological Sciences Scientific Institute for Research and Health Care Bologna Italy

Laboratory for Sleep Disorders St Dimpna Regional Hospital Geel Belgium

Laboratory of Neurogenetics National Institute on Aging National Institutes of Health Bethesda MD

Me Mountain View CA

Montreal Neurological Institute McGill University Montreal Quebec Canada

National Reference Center for Narcolepsy Sleep Unit Department of Neurology Gui de Chauliac Hospital University Hospital of Montpellier University of Montpellier Montpellier France

Nuffield Department of Clinical Neurosciences University of Oxford Oxford United Kingdom

Oxford Parkinson's Disease Center University of Oxford Oxford United Kingdom

Paracelsus Elena Clinic Kassel Germany

Sleep and Neurology Unit Beau Soleil Clinic Montpellier France

Sleep Disorder Unit Carémeau Hospital University Hospital of Nîmes Nîmes France

Sleep Disorders Clinic Department of Neurology Medical University of Innsbruck Innsbruck Austria

Sleep Disorders Unit Pitié Salpêtrière Hospital Institute for Brain and Spinal Cord and Sorbonne University Paris France

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