Genome-wide association study of REM sleep behavior disorder identifies novel loci with distinct polygenic and brain expression effects

Lynne Krohn; Karl Heilbron; Cornelis Blauwendraat; Regina Hertfelder Reynolds; Eric Yu; Konstantin A. Senkevich; Uladzislau Rudakou; Mehrdad A. Estiar; Emil Karl Gustavsson; Kajsa Atterling Brolin; Jennifer A. Ruskey; Kathryn Freeman; Farnaz Asayesh; Ruth Chia; Isabelle Arnulf; Michele T.M. Hu; Jacques Yves Montplaisir; Jean‐François Gagnon; Alex Désautels; Yves A Dauvilliers; Gian Luigi Gigli; Mariarosaria Valente; Francesco Janes; Andrea Bernardini; Birgit Högl; Ambra Stefani; Abubaker Ibrahim; Karel Šonka; David Kemlink; Wolfgang Hermann Oertel

doi:10.1101/2021.09.08.21254232

Genetic & Genomic MedicinemedRxivSep 8, 2021

Preprint

Genome-wide association study of REM sleep behavior disorder identifies novel loci with distinct polygenic and brain expression effects

Lynne Krohn iD, Karl Heilbron iD, Cornelis Blauwendraat iD, Regina Hertfelder Reynolds iD, Eric Yu iD, Konstantin A. Senkevich iD, Uladzislau Rudakou iD, Mehrdad A. Estiar iD, Emil Karl Gustavsson iD, Kajsa Atterling Brolin iD, Jennifer A. Ruskey iD, Kathryn Freeman, Farnaz Asayesh iD, Ruth Chia iD, Isabelle Arnulf iD, Michele T.M. Hu iD, Jacques Yves Montplaisir iD, Jean‐François Gagnon iD, Alex Désautels iD, Yves A Dauvilliers iD, Gian Luigi Gigli iD, Mariarosaria Valente iD, Francesco Janes iD, Andrea Bernardini iD, Birgit Högl iD, , Ziv Gan‐Or iD

Abstract

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

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