OBJECTIVE: To explore potential genetic and/or causal associations between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder. METHODS: We conducted polygenic risk score, genetic correlation, and Mendelian randomization analyses using the latest genome-wide association studies summary statistics and individual genotyping data. Next, a blinded observer examined dopamine transporter imaging binding status-a marker of neurodegeneration-in patients with isolated/idiopathic rapid-eye movement sleep behavior disorder, with (N = 6) and without Post-Traumatic Stress Disorder (N = 32). RESULTS: Polygenic risk scores for Post-Traumatic Stress Disorder were associated with isolated/idiopathic rapid-eye-movement sleep behavior disorder, with each standard deviation increase linked to 14.7% higher odds (odds ratio = 1.15, 95% confidence interval: 1.04 to 1.26, p = 0.005). However, genetic correlation was weak, and Mendelian randomization did not support a potential causal relationship. The proportion of individuals with abnormal dopamine transporter imaging binding status was significantly higher in the Post-Traumatic Stress Disorder group compared to those without the disorder (p=0.01, X2 = 6.62). INTERPRETATION: Polygenic risk scores analysis identified an association between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder, consistent with the result from the small exploratory substudy. The lack of strong genetic correlation or causation may reflect limited sample size. Further research with larger and more diverse cohorts is crucial to clarify the genetic, biological and physiological mechanisms underlying this association.

3rd Faculty of Medicine Charles University Prague Czech Republic

AOVR Verona Italy

Center for Neurology Department of Parkinson Sleep and Movement Disorders University Hospital of Bonn Bonn Germany

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

Cognitive Neuroscience Institute of Neuroscience and Medicine Research Centre Jülich Jülich Germany

Department of Brain and Behavioral Sciences University of Pavia Pavia Italy

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

Department of Clinical Neurosciences Faculty of Medicine P J Safarik University Kosice Slovakia

Department of Computer Engineering Ahrar Institute of Technology and Higher Education Rasht Guilan Iran

Department of Head Neck and Neurosciences Clinical Neurology Unit University Hospital of Udine Udine Italy

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 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 Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Department of Neurology Faculty of Medicine P J Safarik University Kosice Slovakia

Department of Neurology Mayo Clinic Rochester MN USA

Department of Neurology Oregon Health and Science University Portland OR USA

Department of Neurology Philipps University Marburg Germany

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

Department of Neurology St Dimpna Regional Hospital Geel Belgium

Department of Neurology University Hospital of L Pasteur Kosice Slovakia

Department of Neurology University Medical Centre Göttingen Göttingen Germany

Department of Neurology Washington University School of Medicine St Louis Missouri USA

Department of Neuroscience University of Genoa Genoa 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

Department of Sleep Medicine National Institute of Mental Health Klecany Czech Republic

Department of Veteran Affairs VA Portland Health Care System and VISN20 Northwest Mental Illness Research Education and Clinical Center Portland OR USA

Departments of Neuroscience and Clinical Genomics Mayo Clinic Jacksonville FL USA

DIMI Department of Engineering and Medicine of Innovation University of Verona Verona Italy

EuroMov Digital Health in Motion Univ Montpellier IMT Mines Ales Montpellier France

Heinrich Heine Universität Düsseldorf Mathematisch Naturwissenschaftliche Fakultät Institut für Physikalische Biologie Düsseldorf Germany

Institute of Biological Information Processing Structural Biochemistry Forschungszentrum Jülich Jülich Germany

IRCCS Ospedale Policlinico San Martino Genoa Italy

Laboratory for Sleep Disorders St Dimpna Regional Hospital Geel Belgium

National Reference Centre for Orphan Diseases Narcolepsy Rare hypersomnias Sleep Unit Department of Neurology CHU Montpellier Institute for Neurosciences of Montpellier INM Univ Montpellier INSERM Montpellier France

Neurology Service Sleep Centre Hospital Clínic Barcelona Universitat de Barcelona IDIBAPS CIBERNED CB06 05 0018 ISCIII Barcelona Spain

Nuffield Department of Clinical Neurosciences University of Oxford Oxford United Kingdom

Paracelsus Elena Klinik Kassel Germany

Sleep and Neurology Unit Beau Soleil Clinic Montpellier France

Sleep Clinic Pitié Salpêtrière hospital APHP Sorbonne University and Paris Brain institute France

Sleep disorder Unit Carémeau Hospital University Hospital of Nîmes Nîmes France

The Neuro McGill University Montreal QC Canada

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