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

Yuri L Sosero; Karl Heilbron; Pierre Fontanillas; Lucy Norcliffe-Kaufmann; Eric Yu; Uladzislau Rudakou; Jennifer A Ruskey; Kathryn Freeman; Farnaz Asayesh; Kajsa A Brolin; Maria Swanberg; Huw R Morris; Lesley Wu; Raquel Real; Lasse Pihlstrøm; Manuela Tan; Thomas Gasser; Kathrin Brockmann; Hui Liu; Michele T M Hu; Donald G Grosset; Simon J G Lewis; John B Kwok; Pau Pastor; Ignacio Alvarez; Matej Skorvanek; Alexandra Lackova; Miriam Ostrozovicova; Mie Rizig; 23andMe Research Team; International Parkinson’s Disease Genomics Consortium; Lynne Krohn; Ziv Gan-Or

doi:10.1038/s41531-025-01078-w

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

NPJ Parkinsons Dis. 2025 Sep 25;11(1):272. doi: 10.1038/s41531-025-01078-w.

Authors

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.

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.