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

Yuri L Sosero^{1

2}, Karl Heilbron³, Pierre Fontanillas³, Lucy Norcliffe-Kaufmann³, Eric Yu^{1

2}, Uladzislau Rudakou^{1

2}, Jennifer A Ruskey², Kathryn Freeman², Farnaz Asayesh², Kajsa A Brolin⁴, Maria Swanberg⁴, Huw R Morris^{5

6}, Lesley Wu^{5

6}, Raquel Real^{5

6}, Lasse Pihlstrøm⁷, Manuela Tan⁷, Thomas Gasser⁸, Kathrin Brockmann⁸, Hui Liu⁸, Michele T M Hu^{9

10}, Donald G Grosset¹¹, Simon J G Lewis¹², John B Kwok¹², Pau Pastor^{13

14}, Ignacio Alvarez^{13

14}, Matej Skorvanek^{15

16}, Alexandra Lackova^{15

16}, Miriam Ostrozovicova^{15

16}, Mie Rizig¹⁷; 23andMe Research Team; International Parkinson’s Disease Genomics Consortium; Lynne Krohn^{1

2}, Ziv Gan-Or^{18

19

20}

Affiliations

¹ Department of Human Genetics, McGill University, Montréal, QC, Canada.
² The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.
³ 23andMe, Inc., Sunnyvale, CA, USA.
⁴ Lund University, Translational Neurogenetics Unit, Department of Experimental Medical Science, Lund, Sweden.
⁵ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁶ UCL Movement Disorders Centre, University College London, London, UK.
⁷ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁸ Department of Neurodegeneration at Hertie Institute for Clinical Brain Research, Tuebingen, Germany.
⁹ Oxford Parkinson's Disease Centre (OPDC), University of Oxford, Oxford, UK.
¹⁰ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹¹ Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.
¹² Parkinson's Disease Research Clinic, Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
¹³ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain.
¹⁴ Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain.
¹⁵ Department of Neurology, Pavol Jozef Šafárik University in Košice, Košice, Slovakia.
¹⁶ Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovakia.
¹⁷ UCL Queen Square Institute of Neurology, London, UK.
¹⁸ Department of Human Genetics, McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.
¹⁹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.
²⁰ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. ziv.gan-or@mcgill.ca.

PMID: 40998812
PMCID: PMC12462436
DOI: 10.1038/s41531-025-01078-w

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

Yuri L Sosero et al. NPJ Parkinsons Dis. 2025.

. 2025 Sep 25;11(1):272.

doi: 10.1038/s41531-025-01078-w.

Authors

Affiliations

¹ Department of Human Genetics, McGill University, Montréal, QC, Canada.
² The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.
³ 23andMe, Inc., Sunnyvale, CA, USA.
⁴ Lund University, Translational Neurogenetics Unit, Department of Experimental Medical Science, Lund, Sweden.
⁵ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁶ UCL Movement Disorders Centre, University College London, London, UK.
⁷ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁸ Department of Neurodegeneration at Hertie Institute for Clinical Brain Research, Tuebingen, Germany.
⁹ Oxford Parkinson's Disease Centre (OPDC), University of Oxford, Oxford, UK.
¹⁰ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹¹ Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.
¹² Parkinson's Disease Research Clinic, Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
¹³ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain.
¹⁴ Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain.
¹⁵ Department of Neurology, Pavol Jozef Šafárik University in Košice, Košice, Slovakia.
¹⁶ Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovakia.
¹⁷ UCL Queen Square Institute of Neurology, London, UK.
¹⁸ Department of Human Genetics, McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.
¹⁹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.
²⁰ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. ziv.gan-or@mcgill.ca.

PMID: 40998812
PMCID: PMC12462436
DOI: 10.1038/s41531-025-01078-w

Abstract

REM sleep behavior disorder (RBD), is a prodromal synucleinopathy affecting a subset of Parkinson's disease (PD) patients and associated with neuropsychiatric symptoms. This study compared the genetic profiles of 13,020 PD patients with probable RBD (PD + RBD) and 5403 without (PD-RBD) using genome-wide association study (GWAS). RBD was assessed by questionnaires or self-reporting. Potential genetic correlations between neuropsychiatric traits and PD + RBD were assessed using linkage disequilibrium score regression. The top variant in the SNCA locus was associated with PD + RBD (rs10005233-T, OR = 1.21, 95% CI = 1.16-1.27, p = 1.81e-15). PD risk variants in SNCA (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 LRRK2 loci (rs34637584, OR = 0.41, 95% CI = 0.28-0.61, p = 1.04e-5) were associated with reduced PD + RBD risk. A suggestive genetic correlation between attention deficit hyperactivity disorder and PD + RBD was observed but was not statistically significant after correction. These findings highlight genetic distinctions between PD + RBD and PD-RBD, offering insights into PD stratification and potential subtype-specific treatments.

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Conflict of interest statement

Competing interests: Z.G.O. 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. K.H., P.F., L.N.K., and the 23andMe Research Team are employed by and hold stock or stock options in 23andMe. H.M. 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. H.R.M. is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). The remaining authors declare no competing interests.

Figures

**Fig. 1. Manhattan plot of PD with RBD vs. PD without RBD.**
A Manhattan plot showing the results of the GWAS meta-analysis, comparing PD with RBD and PD without RBD, highlighting the *SNCA* and *LRRK2* loci. The Y axis represents the negative logarithm of p value, the X axis represents the chromosomal position of the variants and each dot on the figure represents a SNP. The red line represents the genome-wide Bonferroni-corrected statistical significance threshold (5 × 10⁻⁸), whereas the blue line is the false-discovery rate-corrected significance threshold (5 × 10⁻⁵). Chr chromosome, PD Parkinson’s disease, RBD REM sleep behavior disorder.

**Fig. 2. Genetic correlation between PD with RBD and neuropsychiatric traits.**
The bar plot shows the genetic correlations between PD with RBD and neuropsychiatric traits. The correlation coefficient is illustrated on the X axis. Green bars represent positive correlations whereas red bars negative ones (i.e., a positive correlation of the neuropsychiatric trait with PD without RBD). The asterisks highlight the nominally significant correlations. ALS amyotrophic lateral sclerosis, CD cognitive decline, AD Alzheimer’s disease, PD Parkinson’s disease, DLB dementia with Lewy bodies, Alcohol dep alcohol dependence, cannabis dep cannabis dependence, ADHD attention deficit hyperactivity disorder, OCD obsessive-compulsive disorder, ASD autism spectrum disorder, TS Tourette syndrome, AN anorexia nervosa, PTS post-traumatic syndrome, SCZ schizophrenia, BD bipolar disorder, MDD major depressive disorder.

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References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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