Session Information
Date: Monday, September 23, 2019
Session Title: Genetics
Session Time: 1:45pm-3:15pm
Location: Les Muses Terrace, Level 3
Objective: a). Identify variants in the SNCA locus which affect risk for REM Sleep Behavior Disorder (RBD). b). Test variant effects on rate and type of conversion to Parkinson’s disease (PD) and other synucleinopathies. c). Compare SNCA genetic risk of RBD and the conditions to which it converts.
Background: SNCA is a shared genetic risk factor across synucleinopathies, namely PD{1} and Dementia with Lewy Bodies (DLB),{2} although the top risk loci vary across the conditions. RBD is a prodromal synucleinopathy, seeing 90% of cases convert to synucleinopathy within an average of 10-15 years.{3} RBD presents a unique subtype of PD, presenting more rapid progression of non-motor symptoms and increased cognitive impairment.{4}
Method: Full sequencing and genotyping of SNCA was performed in RBD (n=1,076), PD (n=1,013), and DLB patients (n=415) and controls (n=6,155). Adjusted logistic regression models and a meta-analysis were performed. Variant effects on conversion rate and type were analyzed in 432 RBD cases with available data using chi square and Kaplan-Meier survival analysis.
Results: The top SNCA association signal for RBD lies in the upstream (5’) region at rs10005233 (OR=0.70, p=1.1E-08). 5’ risk variants across synucleinopathies are in linkage disequilibrium with this variant, and risk allele frequencies are consistently elevated in PD or DLB with RBD versus without. A second downstream (3’) RBD-specific association was detected at rs11732740 (OR=1.32, p=4.7E-04). No variants were significantly associated with rate or type of conversion, however 5’ UTR variant rs2583986 showed an average conversion time of 9.4 years for wild type carriers, 6.2 for heterozygous, and 3.5 for homozygous (p=0.0029).
Conclusion: Similar to DLB, upstream (5’) SNCA variants drive the highest association signal for RBD risk. Our findings suggest that the 5’ region of SNCA may affect cognitive components of synucleinopathy.
References: 1. Nalls, Mike A., et al. “Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease.” Nature genetics 46.9 (2014): 989. 2. Guerreiro, Rita, et al. “Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study.” The Lancet Neurology 17.1 (2018): 64-74. 3. Iranzo, Alex, Joan Santamaria, and Eduardo Tolosa. “Idiopathic rapid eye movement sleep behaviour disorder: diagnosis, management, and the need for neuroprotective interventions.” The Lancet Neurology 15.4 (2016): 405-419. 4. Fereshtehnejad, Seyed-Mohammad, et al. “New clinical subtypes of Parkinson disease and their longitudinal progression: a prospective cohort comparison with other phenotypes.” JAMA neurology 72.8 (2015): 863-873.
To cite this abstract in AMA style:
L. Krohn, R. Wu, J. Ruskey, S. Laurent, L. Philstrom, I. Arnulf, M. Hu, Y. Dauvilliers, B. Hogl, A. Stefani, E. Holzknecht, C. Monaca, A. Beatriz, G. Plazzi, E. Antelmi, L. Ferini-Strambi, A. Heidbreder, V. Cochen, B. Mollenhauer, K. Sonka, M. Figorilli, F. Dijkstra, M. Viaene, W. Oertel, J. Gagnon, M. Nalls, C. Blauwendraat, A. Singleton, A. Desautels, J. Montplaisir, O. Ross, B. Boeve, N. Dupre, E. Fon, R. Postuma, G. Rouleau, Z. Gan-Or. Fine-mapping of SNCA variants in REM sleep behavior disorder identifies distinct associations [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/fine-mapping-of-snca-variants-in-rem-sleep-behavior-disorder-identifies-distinct-associations/. Accessed December 7, 2023.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/fine-mapping-of-snca-variants-in-rem-sleep-behavior-disorder-identifies-distinct-associations/