Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Lynne Krohn; Karl Heilbron; Cornelis Blauwendraat; Regina H Reynolds; Eric Yu; Konstantin Senkevich; Uladzislau Rudakou; Mehrdad A Estiar; Emil K Gustavsson; Kajsa Brolin; Jennifer A Ruskey; Kathryn Freeman; Farnaz Asayesh; Ruth Chia; Isabelle Arnulf; Michele T M Hu; Jacques Y Montplaisir; Jean-François Gagnon; Alex Desautels; Yves Dauvilliers; Gian Luigi Gigli; Mariarosaria Valente; Francesco Janes; Andrea Bernardini; Birgit Högl; Ambra Stefani; Abubaker Ibrahim; Karel Šonka; David Kemlink; Wolfgang Oertel; Annette Janzen; Giuseppe Plazzi; Francesco Biscarini; Elena Antelmi; Michela Figorilli; Monica Puligheddu; Brit Mollenhauer; Claudia Trenkwalder; Friederike Sixel-Döring; Valérie Cochen De Cock; Christelle Charley Monaca; Anna Heidbreder; Luigi Ferini-Strambi; Femke Dijkstra; Mineke Viaene; Beatriz Abril; Bradley F Boeve; 23andMe Research Team; Sonja W Scholz; Mina Ryten; Sara Bandres-Ciga; Alastair Noyce; Paul Cannon; Lasse Pihlstrøm; Mike A Nalls; Andrew B Singleton; Guy A Rouleau; Ronald B Postuma; Ziv Gan-Or

doi:10.1038/s41467-022-34732-5

Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Nat Commun. 2022 Dec 5;13(1):7496. doi: 10.1038/s41467-022-34732-5.

Authors

Lynne Krohn^{1

2}, Karl Heilbron³, Cornelis Blauwendraat⁴, Regina H Reynolds^{5

6}, Eric Yu^{1

2}, Konstantin Senkevich^{1

2}, Uladzislau Rudakou^{1

2}, Mehrdad A Estiar^{1

2}, Emil K Gustavsson^{6

7}, Kajsa Brolin⁸, Jennifer A Ruskey², Kathryn Freeman², Farnaz Asayesh², Ruth Chia⁴, Isabelle Arnulf⁹, Michele T M Hu^{10

11}, Jacques Y Montplaisir^{12

13}, Jean-François Gagnon^{12

14}, Alex Desautels^{12

15}, Yves Dauvilliers¹⁶, Gian Luigi Gigli¹⁷, Mariarosaria Valente^{17

18}, Francesco Janes¹⁷, Andrea Bernardini¹⁷, Birgit Högl¹⁹, Ambra Stefani¹⁹, Abubaker Ibrahim¹⁹, Karel Šonka²⁰, David Kemlink²⁰, Wolfgang Oertel²¹, Annette Janzen²¹, Giuseppe Plazzi^{22

23}, Francesco Biscarini²⁴, Elena Antelmi^{23

25}, Michela Figorilli²⁶, Monica Puligheddu²⁶, Brit Mollenhauer^{27

28}, Claudia Trenkwalder^{27

28}, Friederike Sixel-Döring^{21

27}, Valérie Cochen De Cock^{29

30}, Christelle Charley Monaca³¹, Anna Heidbreder³², Luigi Ferini-Strambi³³, Femke Dijkstra^{34

35

36}, Mineke Viaene^{34

35}, Beatriz Abril³⁷, Bradley F Boeve³⁸; 23andMe Research Team; Sonja W Scholz^{39

40}, Mina Ryten^{6

7}, Sara Bandres-Ciga⁴, Alastair Noyce^{41

42}, Paul Cannon³, Lasse Pihlstrøm⁴³, Mike A Nalls^{44

45}, Andrew B Singleton^{4

45}, Guy A Rouleau^{1

2

46}, Ronald B Postuma^{2

46}, Ziv Gan-Or^{47

48

49}

Collaborators

23andMe Research Team:
Stella Aslibekyan, Adam Auton, Elizabeth Babalola, Robert K Bell, Jessica Bielenberg, Katarzyna Bryc, Emily Bullis, Daniella Coker, Gabriel Cuellar Partida, Devika Dhamija, Sayantan Das, Sarah L Elson, Teresa Filshtein, Kipper Fletez-Brant, Pierre Fontanillas, Will Freyman, Pooja M Gandhi, Barry Hicks, David A Hinds, Ethan M Jewett, Yunxuan Jiang, Katelyn Kukar, Keng-Han Lin, Maya Lowe, Jey C McCreight, Matthew H McIntyre, Steven J Micheletti, Meghan E Moreno, Joanna L Mountain, Priyanka Nandakumar, Elizabeth S Noblin, Jared O'Connell, Aaron A Petrakovitz, G David Poznik, Morgan Schumacher, Anjali J Shastri, Janie F Shelton, Jingchunzi Shi, Suyash Shringarpure, Vinh Tran, Joyce Y Tung, Xin Wang, Wei Wang, Catherine H Weldon, Peter Wilton, Alejandro Hernandez, Corinna Wong, Christophe Toukam Tchakouté

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 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁶ Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK.
⁷ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
⁸ Lund University, Translational Neurogenetics Unit, Department of Experimental Medical Science, Lund, Sweden.
⁹ Sleep Disorders Unit, Pitié Salpêtrière Hospital, APHP-Sorbonne, Paris Brain Insitute and Sorbonne University, Paris, France.
¹⁰ Oxford Parkinson's Disease Centre (OPDC), University of Oxford, Oxford, UK.
¹¹ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹² Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, Canada.
¹³ Department of Psychiatry, Université de Montréal, Montréal, QC, Canada.
¹⁴ Department of Psychology, Université du Québec à Montréal, Montreal, QC, Canada.
¹⁵ Department of Neurosciences, Université de Montréal, Montréal, QC, Canada.
¹⁶ National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Institute Neuroscience Montpellier Inserm, Montpellier, France.
¹⁷ Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.
¹⁸ Department of Medicine (DAME), University of Udine, Udine, Italy.
¹⁹ Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
²⁰ Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
²¹ Department of Neurology, Philipps-University, Marburg, Germany.
²² Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy.
²³ IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy.
²⁴ Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy.
²⁵ Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
²⁶ Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
²⁷ Paracelsus-Elena-Klinik, Kassel, Germany.
²⁸ Department of Neurology, University Medical Centre Goettingen, Goettingen, Germany.
²⁹ Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France.
³⁰ EuroMov Digital Health in Motion, University of Montpellier IMT Mines Ales, Montpellier, France.
³¹ University Lille North of France, Department of Clinical Neurophysiology and Sleep Center, CHU Lille, Lille, France.
³² Institute of Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany.
³³ Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy.
³⁴ Laboratory for Sleep Disorders, St. Dimpna Regional Hospital, Geel, Belgium.
³⁵ Department of Neurology, St. Dimpna Regional Hospital, Geel, Belgium.
³⁶ Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
³⁷ Sleep disorder Unit, Carémeau Hospital, University Hospital of Nîmes, Nîmes, France.
³⁸ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
³⁹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
⁴⁰ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁴¹ Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
⁴² Department of Clinical and Movement Neurosciences, University College London, Institute of Neurology, London, UK.
⁴³ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁴⁴ Data Tecnica International, Glen Echo, MD, USA.
⁴⁵ Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA.
⁴⁶ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
⁴⁷ Department of Human Genetics, McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.
⁴⁸ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.
⁴⁹ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. ziv.gan-or@mcgill.ca.

Abstract

Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain
Genome-Wide Association Study
Humans
Parkinson Disease* / genetics
REM Sleep Behavior Disorder* / genetics
Synucleinopathies*

Abstract

Publication types

MeSH terms

Grants and funding