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

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

2022-01-01

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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.