BACKGROUND: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). OBJECTIVE: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. METHODS: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. RESULTS: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. CONCLUSION: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

Centre d'Études Avancées en Médecine du Sommeil Hôpital du Sacré Cœur de Montréal Montréal Québec Canada

Clinical Neurology Unit Department of Neurosciences University Hospital of Udine Udine Italy

Department of Biomedical and Neuromotor Sciences Alma Mater Studiorum University of Bologna Bologna Italy

Department of Clinical Neurophysiology and Sleep Center University Lille North of France CHU Lille Lille France

Department of Human Genetics McGill University Montréal Québec Canada

Department of Medical Sciences and Public Health Sleep Disorder Research Center University of Cagliari Cagliari Italy

Department of Medicine University of Udine Udine Italy

Department of Neurological Sciences Università Vita Salute San Raffaele Milan Italy

Department of Neurology and Centre of Clinical Neuroscience Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Neurology and Neurosurgery McGill University Montréal Québec Canada

Department of Neurology Mayo Clinic Rochester Minnesota USA

Department of Neurology Philipps University Marburg Germany

Department of Neurology St Dimpna Regional Hospital Geel Belgium

Department of Neurology University Hospital Antwerp Edegem Belgium

Department of Neurology University Medical Centre Göttingen Göttingen Germany

Department of Neurosciences Université de Montréal Montréal Québec Canada

Department of Psychiatry Université de Montréal Montréal Québec Canada

Department of Psychology Université du Québec à Montréal Montréal Québec Canada

Department of Sleep Medicine and Neuromuscular Disorders University of Müenster Müenster Germany

EuroMov University of Montpellier Montpellier France

IRCCS Institute of Neurological Sciences of Bologna Bologna Italy

Laboratory for Sleep Disorders St Dimpna Regional Hospital Geel Belgium

Montreal Neurological Institute McGill University Montréal Québec Canada

National Reference Center for Narcolepsy Sleep Unit Department of Neurology Gui de Chauliac Hospital CHU Montpellier University of Montpellier Montpellier France

Neurology Unit Movement Disorders Division Department of Neurosciences Biomedicine and Movement Sciences University of Verona Verona Italy

Nuffield Department of Clinical Neurosciences University of Oxford Oxford United Kingdom

Oxford Parkinson's Disease Centre University of Oxford Oxford United Kingdom

Paracelsus Elena Klinik Kassel Germany

Sleep and Neurology Unit Beau Soleil Clinic Montpellier France

Sleep Disorder Unit Carémeau Hospital University Hospital of Nîmes Nîmes France

Sleep Disorders Clinic Department of Neurology Medical University of Innsbruck Innsbruck Austria

Sleep Disorders Unit Pitié Salpêtrière Hospital Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière and Sorbonne University Paris France

See more in PubMed

Högl B, Stefani A, Videnovic A. Idiopathic REM sleep behaviour disorder and neurodegeneration-An update. Nat Rev Neurol 2018;14(1):40.

Postuma RB, Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain 2019;142(3):744-759.

Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. The Lancet Neurology 2019;18(12):1091-1102.

Gan-Or Z, Alcalay RN, Rouleau GA, Postuma RB. Sleep disorders and Parkinson disease; lessons from genetics. Sleep Med Rev 2018;41:101-112.

Chenbhanich J, Sringean J, Bhidayasiri R. Beyond the classic Segawa disease, GCH1-associated neurodegenerative parkinsonism: practical considerations for physicians. J Mov Disord 2017;10(2):102.

Kilarski LL, Pearson JP, Newsway V, et al. Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease. Mov Disord 2012;27(12):1522-1529.

Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson's disease. Lancet Neurol 2020;19(2):170-178.

Usenovic M, Tresse E, Mazzulli JR, Taylor JP, Krainc D. Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity. J Neurosci 2012;32(12):4240-4246.

Conedera S, Apaydin H, Li Y, et al. FBXO7 mutations in Parkinson's disease and multiple system atrophy. Neurobiol Aging 2016;40:192.

Guo Y-P, Tang B-S, Guo J-F. PLA2G6-associated neurodegeneration (PLAN): review of clinical phenotypes and genotypes. Front Neurol 2018;9:1100.

Gan-Or Z, Mirelman A, Postuma RB, et al. GBA mutations are associated with rapid eye movement sleep behavior disorder. Ann Clin Transl Neurol 2015;2(9):941-945.

Krohn L, Ruskey JA, Rudakou U, et al. GBA variants in REM sleep behavior disorder: a multicenter study. Neurology 2020;95(8):e1008-e1016.

Gan-Or Z, Amshalom I, Kilarski LL, et al. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology 2015;84(9):880-887.

Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009;361(17):1651-1661.

Nalls MA, Duran R, Lopez G, et al. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol 2013;70(6):727-735.

Heckman MG, Soto-Ortolaza AI, Contreras MYS, et al. LRRK2 variation and dementia with Lewy bodies. Parkinson Relat Disord 2016;31:98-103.

Bencheikh BOA, Ruskey JA, Arnulf I, et al. LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder. Parkinson Relat Disord 2018;52:98-101.

Dickson DW, Heckman MG, Murray ME, et al. APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology 2018;91(12):e1182-e1195.

Chang D, Nalls MA, Hallgrímsdóttir IB, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci. Nat Genet 2017;49(10):1511.

Li J, Ruskey JA, Arnulf I, et al. Full sequencing and haplotype analysis of MAPT in Parkinson's disease and rapid eye movement sleep behavior disorder. Mov Disord 2018;33(6):1016-1020.

Gan-Or Z, Montplaisir JY, Ross JP, et al. The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder. Neurobiol Aging 2017;49:218.

Krohn L, Wu RY, Heilbron K, et al. Fine-mapping of SNCA in rapid eye movement sleep behavior disorder and overt Synucleinopathies. Ann Neurol 2020;87(4):584-598.

Krohn L, Öztürk TN, Vanderperre B, et al. Genetic, structural, and functional evidence link TMEM175 to synucleinopathies. Ann Neurol 2020;87(1):139-153.

O'Roak BJ, Vives L, Fu W, et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 2012;338(6114):1619-1622.

Lee S, Emond MJ, Bamshad MJ, et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet 2012;91(2):224-237.

Lücking CB, Dürr A, Bonifati V, et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000;342(21):1560-1567.

Yu E, Rudakou U, Krohn L, et al. Analysis of heterozygous prkn variants and copy-number variations in parkinson's disease. Mov Disord 2020. https://doi.org/10.1002/mds.28299

Reed X, Bandrés-Ciga S, Blauwendraat C, Cookson MR. The role of monogenic genes in idiopathic Parkinson's disease. Neurobiol Dis 2019;124:230-239.

Schneider SA, Alcalay RN. Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature. Mov Disord 2017;32(11):1504-1523.

Samaranch L, Lorenzo-Betancor O, Arbelo JM, et al. PINK1-linked parkinsonism is associated with Lewy body pathology. Brain 2010;133(4):1128-1142.

Takanashi M, Li Y, Hattori N. Absence of Lewy pathology associated with PINK1 homozygous mutation. Neurology 2016;86(23):2212-2213.

Fernández-Santiago R, Iranzo A, Gaig C, et al. Absence of LRRK2 mutations in a cohort of patients with idiopathic REM sleep behavior disorder. Neurology 2016;86(11):1072-1073.

Zhang J, Xu C-Y, Liu J. Meta-analysis on the prevalence of REM sleep behavior disorder symptoms in Parkinson's disease. BMC Neurol 2017;17(1):1-6.

Zhang X, Sun X, Wang J, Tang L, Xie A. Prevalence of rapid eye movement sleep behavior disorder (RBD) in Parkinson's disease: a meta and meta-regression analysis. Neurol Sci 2017;38(1):163-170.

Jiang H, Huang J, Shen Y, et al. RBD and neurodegenerative diseases. Mol Neurobiol 2017;54(4):2997-3006.

Lesage S, Condroyer C, Klebe S, et al. Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology 2012;78(18):1449-1450.

Kumar KR, Weissbach A, Heldmann M, et al. Frequency of the D620N mutation in VPS35 in Parkinson disease. Arch Neurol 2012;69(10):1360-1364.