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

Krohn, L.; Heilbron, K.; Blauwendraat, C.; Reynolds, R. H.; Yu, E.; Senkevich, K.; Rudakou, U.; Estiar, M. A.; Gustavsson, E. K.; Brolin, K.; Ruskey, J. A.; Freeman, K.; Asayesh, F.; Chia, R.; Arnulf, I.; M. T. M., Hu; Montplaisir, J. Y.; Gagnon, J. -F.; Desautels, A.; Dauvilliers, Y.; Gigli, G. L.; Valente, M.; Janes, F.; Bernardini, A.; Hogl, B.; Stefani, A.; Ibrahim, A.; Sonka, K.; Kemlink, D.; Oertel, W.; Janzen, A.; Plazzi, G.; Biscarini, F.; Antelmi, E.; Figorilli, M.; Puligheddu, M.; Mollenhauer, B.; Trenkwalder, C.; Sixel-Doring, F.; Cochen De Cock, V.; Monaca, C. C.; Heidbreder, A.; Ferini-Strambi, L.; Dijkstra, F.; Viaene, M.; Abril, B.; Boeve, B. F.; Aslibekyan, S.; Auton, A.; Babalola, E.; Bell, R. K.; Bielenberg, J.; Bryc, K.; Bullis, E.; Coker, D.; Partida, G. C.; Dhamija, D.; Das, S.; Elson, S. L.; Filshtein, T.; Fletez-Brant, K.; Fontanillas, P.; Freyman, W.; Gandhi, P. M.; Hicks, B.; Hinds, D. A.; Jewett, E. M.; Jiang, Y.; Kukar, K.; Lin, K. -H.; Lowe, M.; Mccreight, J. C.; Mcintyre, M. H.; Micheletti, S. J.; Moreno, M. E.; Mountain, J. L.; Nandakumar, P.; Noblin, E. S.; O'Connell, J.; Petrakovitz, A. A.; Poznik, G. D.; Schumacher, M.; Shastri, A. J.; Shelton, J. F.; Shi, J.; Shringarpure, S.; Tran, V.; Tung, J. Y.; Wang, X.; Wang, W.; Weldon, C. H.; Wilton, P.; Hernandez, A.; Wong, C.; Tchakoute, C. T.; Scholz, S. W.; Ryten, M.; Bandres-Ciga, S.; Noyce, A.; Cannon, P.; Pihlstrom, L.; Nalls, M. A.; Singleton, A. B.; Rouleau, G. A.; Postuma, R. B.; Gan-Or, Z.

doi:10.1038/s41467-022-34732-5

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.