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[Preprint]. 2025 Sep 8:2025.09.05.25335205.

doi: 10.1101/2025.09.05.25335205.

Post-traumatic stress disorder and REM-sleep behavior disorder: exploring genetic associations and causal links

Morvarid Ghamgosar Shahkhali^{1

2}, Lang Liu^{1

2

3}, Mohammad H Ghamgosar Shahkhali⁴, Eric Yu^{1

2}, Farnaz Asayesh^{1

3}, Jamil Ahmad^{1

3}, Meron Teferra^{1

3}, Isabelle Arnulf⁵, Pauline Dodet⁵, Yo-El Ju⁶, Michele T M Hu⁷, Jacques Y Montplaisir^{8

9}, Jean-François Gagnon^{8

10}, Alex Desautels^{8

11}, Abubaker Ibrahim¹², Ambra Stefani¹², Birgit Högl¹², Merve Akrtan-Süzgün¹², Alex Iranzo¹³, Mónica Serradell¹³, Angelica Montini¹³, Gerard Maya¹³, Carles Gaig¹³, Gian Luigi Gigli^{14

15}, Mariarosaria Valente^{14

15}, Francesco Janes^{14

15}, Andrea Bernardini^{14

15}, Yves Dauvilliers¹⁶, Karel Sonka¹⁷, David Kemlink¹⁷, Petr Dusek¹⁷, Michael Sommerauer^{18

19

20}, Gültekin Tamgüney^{21

22}, Michela Figorilli²³, Monica Puligheddu²³, Valerie Cochen De Cock^{24

25}, Wolfgang Oertel²⁶, Annette Janzen²⁶, Elena Antelmi^{27

28}, Brit Mollenhauer^{29

30}, Claudia Trenkwalder^{29

30}, Friederike Sixel-Doring^{26

29}, Michele Terzaghi³¹, Giuseppe Fiamingo^{8

31}, Matej Skorvanek^{32

33

34}, Kristina Kulcsarova^{32

33

34}, Beatriz Abril³⁵, Christelle Charley Monaca³⁶, Luigi Ferini-Strambi³⁷, Jitka Bušková^{38

39}, Beatrice Orso⁴⁰, Pietro Mattioli^{40

41}, Dario Arnaldi^{40

41}, Femke Dijkstra^{42

43

44}, Mineke Viaene^{42

43}, Bradley F Boeve⁴⁵, Owen A Ross⁴⁶, Guy A Rouleau^{1

2

3}, Lee E Neilson^{47

48}, Jonathan E Elliott^{47

48}, Miranda M Lim^{47

48}, Ronald B Postuma^{1

3

8}, Ziv Gan-Or^{1

2

3}

Affiliations

¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada.
² Department of Human Genetics, McGill University, Montréal, QC, Canada.
³ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
⁴ Department of Computer Engineering, Ahrar Institute of Technology and Higher Education, Rasht, Guilan, Iran.
⁵ Sleep Clinic, Pitié Salpêtrière hospital, APHP-Sorbonne University and Paris Brain institute, France.
⁶ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁷ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
⁸ Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.
⁹ Department of Psychiatry, Université de Montréal, Montréal, QC, Canada.
¹⁰ Department of Psychology, Université du Québec à Montréal, Montreal, QC, Canada.
¹¹ Department of Neurosciences, Université de Montréal, Montréal, QC, Canada.
¹² Department of Neurology, Sleep Disorders Clinic, Medical University of Innsbruck, Innsbruck, Austria.
¹³ Neurology Service, Sleep Centre, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain.
¹⁴ Department of Head, Neck and Neurosciences, Clinical Neurology Unit, University Hospital of Udine, Udine, Italy.
¹⁵ Department of Medicine (DMED), University of Udine, Udine, Italy.
¹⁶ 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.
¹⁷ Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
¹⁸ Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁹ Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich, Jülich, Germany.
²⁰ Center for Neurology, Department of Parkinson, Sleep, and Movement Disorders, University Hospital of Bonn, Bonn, Germany.
²¹ Institute of Biological Information Processing - Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany.
²² Heinrich-Heine-Universität Düsseldorf, Mathematisch-Naturwissenschaftliche Fakultät, Institut für Physikalische Biologie, Düsseldorf, Germany.
²³ Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
²⁴ Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France.
²⁵ EuroMov Digital Health in Motion, Univ Montpellier, IMT Mines Ales, Montpellier, France.
²⁶ Department of Neurology, Philipps-University, Marburg, Germany.
²⁷ AOVR, Verona, Italy.
²⁸ DIMI Department of Engineering and Medicine of Innovation, University of Verona, Verona, Italy.
²⁹ Department of Neurology, University Medical Centre Göttingen, Göttingen, Germany.
³⁰ Paracelsus-Elena-Klinik, Kassel, Germany.
³¹ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
³² Department of Neurology, Faculty of Medicine, P. J. Safarik University, Kosice, Slovakia.
³³ Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovakia.
³⁴ Department of Clinical Neurosciences, Faculty of Medicine, P. J. Safarik University, Kosice, Slovakia.
³⁵ Sleep disorder Unit, Carémeau Hospital, University Hospital of Nîmes, Nîmes, France.
³⁶ Department of Clinical Neurophysiology and Sleep Center, University Lille North of France, CHU Lille, Lille, France.
³⁷ Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy.
³⁸ Department of Sleep Medicine, National Institute of Mental Health, Klecany, Czech Republic.
³⁹ Third Faculty of Medicine, Charles University, Prague, Czech Republic.
⁴⁰ Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy.
⁴¹ IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
⁴² Laboratory for Sleep Disorders, St. Dimpna Regional Hospital, Geel, Belgium.
⁴³ Department of Neurology, St. Dimpna Regional Hospital, Geel, Belgium.
⁴⁴ Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
⁴⁵ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁴⁶ Departments of Neuroscience and Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA.
⁴⁷ Department of Neurology, Oregon Health & Science University, Portland, OR, USA.
⁴⁸ Department of Veteran Affairs, VA Portland Health Care System and VISN20 Northwest Mental Illness Research, Education, and Clinical Center, Portland, OR, USA.

PMID: 40963755
PMCID: PMC12440045
DOI: 10.1101/2025.09.05.25335205

Post-traumatic stress disorder and REM-sleep behavior disorder: exploring genetic associations and causal links

Morvarid Ghamgosar Shahkhali et al. medRxiv. 2025.

[Preprint]. 2025 Sep 8:2025.09.05.25335205.

doi: 10.1101/2025.09.05.25335205.

Authors

Affiliations

¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada.
² Department of Human Genetics, McGill University, Montréal, QC, Canada.
³ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
⁴ Department of Computer Engineering, Ahrar Institute of Technology and Higher Education, Rasht, Guilan, Iran.
⁵ Sleep Clinic, Pitié Salpêtrière hospital, APHP-Sorbonne University and Paris Brain institute, France.
⁶ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁷ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
⁸ Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.
⁹ Department of Psychiatry, Université de Montréal, Montréal, QC, Canada.
¹⁰ Department of Psychology, Université du Québec à Montréal, Montreal, QC, Canada.
¹¹ Department of Neurosciences, Université de Montréal, Montréal, QC, Canada.
¹² Department of Neurology, Sleep Disorders Clinic, Medical University of Innsbruck, Innsbruck, Austria.
¹³ Neurology Service, Sleep Centre, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain.
¹⁴ Department of Head, Neck and Neurosciences, Clinical Neurology Unit, University Hospital of Udine, Udine, Italy.
¹⁵ Department of Medicine (DMED), University of Udine, Udine, Italy.
¹⁶ 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.
¹⁷ Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
¹⁸ Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁹ Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich, Jülich, Germany.
²⁰ Center for Neurology, Department of Parkinson, Sleep, and Movement Disorders, University Hospital of Bonn, Bonn, Germany.
²¹ Institute of Biological Information Processing - Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany.
²² Heinrich-Heine-Universität Düsseldorf, Mathematisch-Naturwissenschaftliche Fakultät, Institut für Physikalische Biologie, Düsseldorf, Germany.
²³ Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
²⁴ Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France.
²⁵ EuroMov Digital Health in Motion, Univ Montpellier, IMT Mines Ales, Montpellier, France.
²⁶ Department of Neurology, Philipps-University, Marburg, Germany.
²⁷ AOVR, Verona, Italy.
²⁸ DIMI Department of Engineering and Medicine of Innovation, University of Verona, Verona, Italy.
²⁹ Department of Neurology, University Medical Centre Göttingen, Göttingen, Germany.
³⁰ Paracelsus-Elena-Klinik, Kassel, Germany.
³¹ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
³² Department of Neurology, Faculty of Medicine, P. J. Safarik University, Kosice, Slovakia.
³³ Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovakia.
³⁴ Department of Clinical Neurosciences, Faculty of Medicine, P. J. Safarik University, Kosice, Slovakia.
³⁵ Sleep disorder Unit, Carémeau Hospital, University Hospital of Nîmes, Nîmes, France.
³⁶ Department of Clinical Neurophysiology and Sleep Center, University Lille North of France, CHU Lille, Lille, France.
³⁷ Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy.
³⁸ Department of Sleep Medicine, National Institute of Mental Health, Klecany, Czech Republic.
³⁹ Third Faculty of Medicine, Charles University, Prague, Czech Republic.
⁴⁰ Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy.
⁴¹ IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
⁴² Laboratory for Sleep Disorders, St. Dimpna Regional Hospital, Geel, Belgium.
⁴³ Department of Neurology, St. Dimpna Regional Hospital, Geel, Belgium.
⁴⁴ Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
⁴⁵ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁴⁶ Departments of Neuroscience and Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA.
⁴⁷ Department of Neurology, Oregon Health & Science University, Portland, OR, USA.
⁴⁸ Department of Veteran Affairs, VA Portland Health Care System and VISN20 Northwest Mental Illness Research, Education, and Clinical Center, Portland, OR, USA.

PMID: 40963755
PMCID: PMC12440045
DOI: 10.1101/2025.09.05.25335205

Abstract

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.

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Conflict of interest statement

ZG-O received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua bio, Congruence Therapeutics, Takeda, Jazz pharmaceuticals, EG427, Guidepoint, Lighthouse and Deerfield. BM has received honoraria for consultancy and/or educational presentations from GE, Bial, Roche, Biogen, AbbVie, Desitin and Amprion. BM is member of the executive steering committee of the Parkinson Progression Marker Initiative of the Michael J. Fox Foundation for Parkinson’s Research and has received research funding from Aligning Science Across Parkinson’s disease (ASAP, CRN). AD received research grants from Eisai and Takeda; honoraria from serving on the scientific advisory board of Eisai, Takeda, Paladin Labs, as well as honoraria from speaking engagements from AstraZeneka, Eisai, Jazz Pharma and Paladin Labs. None of the financial disclosures is relevant to the submitted work.

Figures

**Fig 1.**
Mendelian Randomization Estimates for Post-Traumatic Stress Disorder (PTSD) on Isolated/idiopathic rapid-eye movement (REM) sleep behavior disorder (iRBD)

See this image and copyright information in PMC

References

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This is a preprint.

Post-traumatic stress disorder and REM-sleep behavior disorder: exploring genetic associations and causal links

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Post-traumatic stress disorder and REM-sleep behavior disorder: exploring genetic associations and causal links

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Abstract

Conflict of interest statement

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