Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention.

Center for Alzheimer's and Related Dementias National Institutes of Health Bethesda MD USA

Centre d'Études Avancées en Médecine du Sommeil Hôpital du Sacré Cœur de Montréal Montréal QC Canada

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

Data Tecnica International Glen Echo MD USA

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

Department of Biomedical Metabolic and Neural Sciences University of Modena and Reggio Emilia Modena Italy

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

Department of Human Genetics McGill University Montréal QC Canada

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

Department of Medicine University of Udine Udine Italy

Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology University College London London UK

Department of Neurological Sciences Università Vita Salute San Raffaele Milan Italy

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

Department of Neurology and Neurosurgery McGill University Montreal QC Canada

Department of Neurology Antwerp University Hospital Edegem Belgium

Department of Neurology Johns Hopkins University Medical Center Baltimore MD USA

Department of Neurology Mayo Clinic Rochester MN USA

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 Neurology University Medical Centre Goettingen Goettingen Germany

Department of Neurosciences Biomedicine and Movement Sciences University of Verona Verona Italy

Department of Neurosciences Université de Montréal Montréal QC Canada

Department of Psychiatry Université de Montréal Montréal QC Canada

Department of Psychology Université du Québec à Montréal Montreal QC Canada

EuroMov Digital Health in Motion University of Montpellier IMT Mines Ales Montpellier France

Great Ormond Street Institute of Child Health Genetics and Genomic Medicine University College London London UK

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

IRCCS Institute of Neurological Sciences of Bologna 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 USA

Lund University Translational Neurogenetics Unit Department of Experimental Medical Science Lund Sweden

Me Inc Sunnyvale CA USA

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

Neurodegenerative Diseases Research Unit National Institute of Neurological Disorders and Stroke Bethesda MD USA

NIHR Great Ormond Street Hospital Biomedical Research Centre University College London London UK

Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK

Oxford Parkinson's Disease Centre University of Oxford Oxford UK

Paracelsus Elena Klinik Kassel Germany

Preventive Neurology Unit Wolfson Institute of Preventive Medicine Queen Mary University of London London UK

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 APHP Sorbonne Paris Brain Insitute and Sorbonne University Paris France

The Neuro McGill University Montréal QC Canada

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

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HLA in isolated REM sleep behavior disorder and Lewy body dementia

HLA in isolated REM sleep behavior disorder and Lewy body dementia

Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects