Session Information
Date: Monday, October 8, 2018
Session Title: Parkinson's Disease: Genetics
Session Time: 1:15pm-2:45pm
Location: Hall 3FG
Objective: To examine the role of LRRK2 mutations and variants in susceptibility for RBD.
Background: Rapid eye movement (REM)-sleep behavior disorder (RBD) is, in most cases, a prodromal synucleinopathy, likely to progress to either Parkinson’s disease (PD), dementia with Lew-bodies (DLB) or multiple system atrophy (MSA) in rare cases. There is only partial overlap between the genetics of RBD and PD. LRRK2 mutations that are known to cause PD are rare in RBD, yet thus far no comprehensive, full sequencing study of LRRK2 was performed in RBD.
Methods: A total of 350 RBD patients, diagnosed by clinical interview and polysomnography according to the International Classification of Sleep Disorders, version 2 (ICSD-2) criteria, and 869 controls participated in the current study. The full coding sequence, exon-intron boundaries and 5’ and 3’ untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing with molecular inversion probes (MIPs). Regression and burden models were used to examine the association between LRRK2 variants and RBD.
Results: None of the known PD-causing LRRK2 pathogenic mutations was identified in RBD patients. Interestingly, the haplotype that includes the variants p.N551K-p.R1398H-p.K1423K was associated with a reduced RBD risk (OR=0.66, 95% CI 0.44-0.98, p=0.0055 for the tagging p.N551K substitution). In addition, a common variant, p.S1647T, was nominally associated with risk for RBD (OR=1.28, 95% CI 1.05-1.56, p=0.029), but was not significant after correction for multiple comparisons. Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified.
Conclusions: Carriage of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype is associated with a reduced risk for RBD. However, the known PD-causing LRRK2 mutations probably have minor or no role in RBD. Additional studies are needed to replicate these results and to identify the mechanism associated with reduced risk for RBD.
To cite this abstract in AMA style:
B. Ouled Amar-Bencheikh, J. Ruskey, I. Arnulf, Y. Dauvilliers, C. Charley Monaca, V. Cochen De-Cock, JF. Gagnon, D. Spiegelman, M. Hu, B. Högl, A. Stefani, L. Ferini-Strambi, G. Plazzi, E. Antelmi, P. Young, A. Heidbreder, B. Mollenhauer, F. Sixel-Döring, C. Trenkwalder, W. Oertel, J. Montplaisir, R. Postuma, G. Rouleau, Z. Gan-Or. Full sequencing and haplotype analysis reveals LRRK2 protective haplotype in REM sleep behavior disorder [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/full-sequencing-and-haplotype-analysis-reveals-lrrk2-protective-haplotype-in-rem-sleep-behavior-disorder/. Accessed June 14, 2025.« Back to 2018 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/full-sequencing-and-haplotype-analysis-reveals-lrrk2-protective-haplotype-in-rem-sleep-behavior-disorder/