Mollenhauer, Brit

Abstract Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: GBA1 , PLEKHM1 , LRP2 , P2RX1 , and HAP1. Subsequent analysis of these genes in Parkinson’s disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.

ABSTRACT Background Multiple System Atrophy is a rare neurodegenerative disease with alpha‐synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome‐wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy‐confirmed cases. Methods We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results The most strongly disease‐associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P ‐values below 5 × 10 −6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4‐immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4‐mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society