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.

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.

This study was financially supported through grants from the Hilary and Galen Weston Foundation, Michael J. Fox Foundation (MJFF) and the Canadian Consortium on Neurodegeneration in Aging (CCNA). Additionally, the G-Can (GBA1-Canada) Initiative, an open-science collaborative initiative aimed at addressing GBA1 mutation-based Parkinson's disease, has made contributions to this research. G-Can is supported by The Hilary and Galen Weston Foundation, Silverstein Foundation, and J. Sebastian van Berkom and Ghislaine Saucier. This work was supported in part by the Intramural Research Program of the National Institute on Aging (NIA), and the Center for Alzheimer's and Related Dementias (CARD), within the Intramural Research Program of the National Institute on Aging and the National Institute of Neurological Disorders and Stroke (1ZIAAG000546) as well as NIH NIA grants R34 AG056639, U19 AG071754, P50 AG016574, P30 AG062677 and VA RRD RX004822. M Skorvanek and KK received funding from the Slovak Research and Development Agency under contract no. APVV-22-0279, and the EU Renewal and Resilience Plan "Large projects for excellent researchers" under grant No. 09I03-03-V03-00007. The iRBD cohort study at First Medical Faculty (Prague, Czechia) is supported by the Czech Health Research Council (grant NU21-04-00535) and the National Institute for Neurological Research (Project No. LX22NPO5107), funded by the European Union - Next Generation EU. This research used the NeuroHub infrastructure and was undertaken thanks in part to funding from the Canada First Research Excellence Fund, awarded through the Healthy Brains, Healthy Lives initiative at McGill University, Calcul Quebec and Compute Canada. This research has been conducted using the UK Biobank Resource under Application Number 45551. The UKB cohort was accessed using Neurohub (https://www.mcgill.ca/hbhl/neurohub ). ZG-O is supported by the Fonds de recherche du Quebec - Sante (FRQS) Chercheurs-boursiers award and is a William Dawson Scholar. MGS is supported by a graduate student award, Jeanne Timmins Costello Award. J.-F.G. holds a Canada Research Chair in Cognitive Decline in Pathological Aging. We acknowledge the contributions of Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group (PGC-PTSD) for support with data sharing.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The UKB genotyping data were accessed through NeuroHub (https://www.mcgill.ca/hbhl/neurohub). Due to the sensitive nature of potentially identifiable protected health information of participants, deidentified clinical data will be made available upon request pursuant to institutional approvals for a Data Use Agreement or equivalent agreement as appropriate.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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The iRBD summary statistics are available on GWAS catalog (https://www.ebi.ac.uk/gwas/, study accession GCST90204200). PTSD summary statistics are publicly available on PGC website (https://pgc.unc.edu/for-researchers/download-results/ , accession ID ptsd2024). The UKB genotyping data were accessed through NeuroHub (https://www.mcgill.ca/hbhl/neurohub). Genotyping data from dbGaP (https://www.ncbi.nlm.nih.gov/gap/) are available through the NeuroGenetics Research Consortium (NGRC) (dbGaP accession: phs000196.v3.p1) and the National Institute of Neurological Disorders and Stroke (NINDS) Genome-Wide Genotyping in Parkinson's Disease study (dbGaP accession: phs000089.v4.p2). Due to the sensitive nature of potentially identifiable protected health information of participants, deidentified clinical data will be made available upon request pursuant to institutional approvals for a Data Use Agreement or equivalent agreement as appropriate. The code supporting the findings of this study will be made publicly available on GitHub upon publication at: https://github.com/mghamg/PTSD-RBD-Study

https://www.ebi.ac.uk/gwas/

https://pgc.unc.edu/for-researchers/download-results/

https://www.mcgill.ca/hbhl/neurohub

https://www.ncbi.nlm.nih.gov/gap/

https://github.com/mghamg/PTSD-RBD-Study