Genome-wide association study of REM sleep behavior disorder in Parkinson's disease

Objective: REM sleep behavior disorder (RBD) is a prodromal synucleinopathy, reported in a subset of Parkinson s disease (PD) patients, and associated with neuropsychiatric symptoms in PD. We aimed to compare the genetic background of PD patients with probable RBD (PD+RBD) and PD patients without probable RBD (PD-RBD). Furthermore, we examined genetic correlations and potential causal associations between multiple neuropsychiatric traits and PD+RBD. Methods: We performed a genome-wide association study (GWAS) including 5,403 PD+RBD and 13,020 PD-RBD. To test for genetic correlations and potential causal associations between neuropsychiatric traits and PD+RBD, we used linkage disequilibrium score regression and Mendelian randomization. Results: The SNCA locus was associated with PD+RBD compared to PD-RBD (rs10005233, OR=1.21, 95% CI=1.16-1.27, p=1.81e-15). Further examination of known genetic loci associated with PD from the most recent PD GWAS in Europeans and Asians identified additional variants associated with reduced risk for PD+RBD: two in the SNCA locus (rs5019538-G, OR=0.85, 95% CI=0.81-0.89, p=2.46E-10; rs356182-G, OR=0.89, 95% CI=0.84-0.95, p=0.0001), and one in the LRRK2 locus (rs34637584, p.G2019S, OR=0.41, 95% CI=0.28-0.61, p=1.04E-5). We found a potential genetic correlation between attention deficit hyperactivity disorder (ADHD) and PD+RBD, which was not statistically significant after correction for multiple comparisons. No causative association emerged between PD and neuropsychiatric traits. Interpretation: Genetic variants contribute to the occurrence of RBD in PD, further distinguishing between the PD+RBD and PD-RBD subtypes. Understanding the mechanisms underlying these genetic associations could contribute to the development of subtype-specific treatments. ### Competing Interest Statement ZGO has received consulting fees from Lysosomal Therapeutics Inc., Idorsia, Prevail Therapeutics, Denali, Ono Therapeutics, Neuron23, Handl Therapeutics, UBC, Bial Biotech Inc., Bial, Deerfield, Guidepoint, Lighthouse and Inception Sciences (now Ventus). None of these companies were involved in any parts of preparing, drafting and publishing this study. KH, PF, LNK, and the 23andMe Research Team are employed by and hold stock or stock options in 23andMe. HM is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia and Amylyx ; lecture fees/honoraria - BMJ, Kyowa Kirin, Movement Disorders Society. Research Grants from Parkinson s UK, Cure Parkinson s Trust, PSP Association, Medical Research Council, Michael J Fox Foundation. Dr Morris is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140) Remaining authors declare no competing interests. ### Funding Statement This work was financially supported by the Michael J. Fox Foundation, Parkinson s Society Canada, the Canadian Consortium on Neurodegeneration in Aging (CCNA), and the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program. ZGO is supported by the Fonds de recherche du Quebec - Sante (FRQS) Chercheurs-boursiers award, and is a William Dawson Scholar. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of McGill University gave ethical approval for this work. 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. Yes 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. The codes used for the analyses are available on https://github.com/daskrohn/RBD_GWAS and https://github.com/gan-orlab. 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