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, 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 and Ziv Gan-Or ()
Additional contact information
Lynne Krohn: McGill University
Karl Heilbron: 23andMe, Inc.
Cornelis Blauwendraat: National Institutes of Health
Regina H. Reynolds: University College London
Eric Yu: McGill University
Konstantin Senkevich: McGill University
Uladzislau Rudakou: McGill University
Mehrdad A. Estiar: McGill University
Emil K. Gustavsson: University College London
Kajsa Brolin: Department of Experimental Medical Science
Jennifer A. Ruskey: McGill University
Kathryn Freeman: McGill University
Farnaz Asayesh: McGill University
Ruth Chia: National Institutes of Health
Isabelle Arnulf: Paris Brain Insitute and Sorbonne University
Michele T. M. Hu: University of Oxford
Jacques Y. Montplaisir: Hôpital du Sacré-Cœur de Montréal
Jean-François Gagnon: Hôpital du Sacré-Cœur de Montréal
Alex Desautels: Hôpital du Sacré-Cœur de Montréal
Yves Dauvilliers: Institute Neuroscience Montpellier Inserm
Gian Luigi Gigli: University Hospital of Udine
Mariarosaria Valente: University Hospital of Udine
Francesco Janes: University Hospital of Udine
Andrea Bernardini: University Hospital of Udine
Birgit Högl: Medical University of Innsbruck
Ambra Stefani: Medical University of Innsbruck
Abubaker Ibrahim: Medical University of Innsbruck
Karel Šonka: First Faculty of Medicine and General University Hospital
David Kemlink: First Faculty of Medicine and General University Hospital
Wolfgang Oertel: Philipps-University
Annette Janzen: Philipps-University
Giuseppe Plazzi: University of Modena and Reggio-Emilia
Francesco Biscarini: University of Bologna
Elena Antelmi: Institute of Neurological Sciences of Bologna
Michela Figorilli: University of Cagliari
Monica Puligheddu: University of Cagliari
Brit Mollenhauer: Paracelsus-Elena-Klinik
Claudia Trenkwalder: Paracelsus-Elena-Klinik
Friederike Sixel-Döring: Philipps-University
Valérie Cochen De Cock: Beau Soleil Clinic
Christelle Charley Monaca: CHU Lille
Anna Heidbreder: University of Münster
Luigi Ferini-Strambi: Università Vita-Salute San Raffaele
Femke Dijkstra: St. Dimpna Regional Hospital
Mineke Viaene: St. Dimpna Regional Hospital
Beatriz Abril: University Hospital of Nîmes
Bradley F. Boeve: Department of Neurology, Mayo Clinic
Sonja W. Scholz: National Institute of Neurological Disorders and Stroke
Mina Ryten: University College London
Sara Bandres-Ciga: National Institutes of Health
Alastair Noyce: Queen Mary University of London
Paul Cannon: 23andMe, Inc.
Lasse Pihlstrøm: Oslo University Hospital
Mike A. Nalls: Data Tecnica International
Andrew B. Singleton: National Institutes of Health
Guy A. Rouleau: McGill University
Ronald B. Postuma: McGill University
Ziv Gan-Or: McGill University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34732-5

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