Shared Pathogenic Pathways Between REM Sleep Behavior Disorder and Neurodegenerative and Psychiatric Disorders

Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: <i>GBA1</i>, <i>PLEKHM1</i>, <i>LRP2</i>, <i>P2RX1</i>, and <i>HAP1.</i> Subsequent analysis of these genes in Parkinson's disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.

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medRxiv
Published
2026-02-05
DOI
https://doi.org/10.64898/2026.02.05.26345599
Primary Topic
Sleep and Wakefulness Research
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article
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0.00

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article

Shared Pathogenic Pathways Between REM Sleep Behavior Disorder and Neurodegenerative and Psychiatric Disorders

Abubaker Ibrahim, Daria Prilutsky, A. Stefani, Farnaz Asayesh et al.
medRxiv
Sleep and Wakefulness Research
article

Shared Pathogenic Pathways Between REM Sleep Behavior Disorder and Neurodegenerative and Psychiatric Disorders

Abubaker Ibrahim, Daria Prilutsky, A. Stefani, Farnaz Asayesh, Karel Šonka, V. De Cock, Angelica Montini, Pietro Mattioli, Jonghun Lee, Francesco Janes, P. Dodet, Andrea Bernardini, Saeid Amiri, Michael Sommerauer, Giuseppe Fiamingo, Emma N. Somerville, Matěj Škorvánek, Zih-Hua Fang, Birgit Högl, Mariarosaria Valente, Anna Heidbreder, Ziv Gan-Or, Beatriz Abril, Yo-El S Ju, Merve Aktan-Süzgün, Mònica Serradell, Meron Teferra, D. Arnaldi, P. Dusek, M. Figorilli, G. Plazzi, E. Antelmi, G. Mayà, B. Orso, A. Desautels, J. Bušková, Sinah Röttgen, Michele Terzaghi, Monica Puligheddu, Jamil Ahmad, Gian Luigi Gigli, Ronald B. Postuma, Friederike Sixel-Doring, Brit Mollenhauer, Luigi Ferini-Strambi, Francsesco Biscarini, Bradley F. Boeve, Shih-Ying Wu, Owen A. Ross, Yves Dauvilliers, Cornelis Blauwendraat, Isabelle Arnulf, Lang Liu, Michele T.M. Hu, Carles Gaig, Claudia Trenkwalder, Kristina Kulcsarova, David Kemlink, Alex Iranzo, Zhao Zhang, Guy A. Rouleau
article en

Abstract

Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: <i>GBA1</i>, <i>PLEKHM1</i>, <i>LRP2</i>, <i>P2RX1</i>, and <i>HAP1.</i> Subsequent analysis of these genes in Parkinson's disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.

medRxiv
University of Verona (IT), University of Modena and Reggio Emilia (IT), University of Udine (IT), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), Innsbruck Medical University (AT), Vita-Salute San Raffaele University (IT), Inserm (FR), Philipps University of Marburg (DE), Forschungszentrum Jülich (DE), University of Cagliari (IT), University of Cologne (DE), Université de Montpellier (FR), Washington University in St. Louis (US), University of Pavol Jozef Šafárik (SK), Charles University (CZ), University of Pavia (IT), University Hospital Bonn (DE), University Hospitals of the Ruhr-University of Bochum (DE), German Center for Neurodegenerative Diseases (DE), Sorbonne Université (FR), University of Oxford (GB), Azienda Ospedaliera di Perugia (IT), Assistance Publique – Hôpitaux de Paris (FR), Quantitative BioSciences (US), Clinique du Millénaire (FR), Centre Hospitalier Universitaire de Nîmes (FR), Univerzitná Nemocnica Louisa Pasteura (SK), National Institute of Neurological Disorders and Stroke (US), Hospital Clínic de Barcelona (ES), Universitätsmedizin Göttingen (DE), Institute of Neurological Sciences (IT), Institut des Sciences Cognitives Marc Jeannerod (FR), Paracelsus Elena Klinik Kassel (DE), Mayo Clinic in Arizona (US), National Institute on Aging (US), Takeda (United States) (US), Hôpital du Sacré-Cœur de Montréal (CA), Mayo Clinic in Florida (US), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University Hospital Cologne (DE), Canadian Sleep & Circadian Network (CA), National Institute of Mental Health (CZ), University College London (GB), McGill University (CA), Université de Nîmes (FR), Université de Montréal (CA), University of Göttingen (DE), University of Genoa (IT), Ruhr University Bochum (DE), University of Bologna (IT)
Michael J. Fox Foundation for Parkinson's Research, McGill University, Compute Canada, Consortium canadien en neurodégénérescence associée au vieillissement, European Commission, Agentúra na Podporu Výskumu a Vývoja, Agentura Pro Zdravotnický Výzkum České Republiky, Canada First Research Excellence Fund, National Institutes of Health, Fonds de Recherche du Québec - Santé, National Institute on Aging
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