Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects.
Krohn L., Heilbron K., Blauwendraat C., Reynolds RH., Yu E., Senkevich K., Rudakou U., Estiar MA., Gustavsson EK., Brolin K., Ruskey JA., Freeman K., Asayesh F., Chia R., Arnulf I., Hu MTM., Montplaisir JY., Gagnon J-F., Desautels A., Dauvilliers Y., Gigli GL., Valente M., Janes F., Bernardini A., Högl B., Stefani A., Ibrahim A., Šonka K., Kemlink D., Oertel W., Janzen A., Plazzi G., Biscarini F., Antelmi E., Figorilli M., Puligheddu M., Mollenhauer B., Trenkwalder C., Sixel-Döring F., Cochen De Cock V., Monaca CC., Heidbreder A., Ferini-Strambi L., Dijkstra F., Viaene M., Abril B., Boeve BF., 23andMe Research Team None., Scholz SW., Ryten M., Bandres-Ciga S., Noyce A., Cannon P., Pihlstrøm L., Nalls MA., Singleton AB., Rouleau GA., Postuma RB., Gan-Or Z.
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.