Objective: To study the role of SNCA variants in REM sleep Behavior Disorder (RBD) and progression to synucleinopathies.

Background: Individuals with properly diagnosed idiopathic RBD will progress to a synucleinopathy within 10-12 years in average. Coding variants in SNCA may cause familial PD or DLB, and non-coding variants are associated with risk for PD and DLB.

Methods: A total of 351 individuals  with RBD, 525 individuals with PD and 691 controls were studied. Data on SNCA variants was produced using the NeuroX SNP chip (Illumina). The entire coding sequence of SNCA was captured and sequenced using molecular inversion probes (MIPs).

Results: The strongest SNCA SNPs associated with RBD were at the 5’ of the gene (strongest marker rs2737014, p=2.9xE-3). In PD they were around the 3’ (rs356182, p=3.9E-4). In PD, no point mutations were identified, but two controls carried the p.N122T variant (predicted to be benign). In the 3’ UTR region of SNCA, rs3857053 and rs1045722 were in full Linkage Disequilibrium. and were associated with an increased risk for PD (allele frequency in PD and controls 0.081 and 0.059, respectively, OR 1.39, 95% CI 1.02-1.91, p=0.03), consistent with its effect in PDgene (OR 1.34, p=4.64E-25). This association did not exist in RBD. There was a trend towards a faster progression from RBD to synucleinopathies in carriers of the rs2245804 SNP in the 5’ UTR of SNCA. This SNP was nominally associated with both AAO of RBD (p=0.048) and progression rate (p=0.015). The occurrence of probable RBD in a subset of our PD cohort with available data (n=260) was associated with both rs1045722 and rs2301135. Carriage of either one or two alleles (dominant model) of the rs1045722 SNP was associated with an OR of 2.78 for probable RBD among PD patients (95%CI 1.35 – 5.75, p=0.005). Homozygous carriage of the rs2301135 SNP (recessive model) was associated with an OR of 1.95 for probable RBD among PD patients (95% CI 1.004 – 3.78, p=0.047).

Conclusions: SNCA variants are associated with both RBD and PD, but in PD they are concentrated around the 3’ of the gene, and in RBD they are at the 5’. This may suggest that RBD is genetically more similar to DLB, in which the associated markers are also at the 5’ of SNCA. The potential associations with rate of progression from RBD to PD, with AAO of RBD and with probable RBD in the PD cohort, need to be replicated in additional cohorts.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/full-sequencing-and-gwas-markers-analysis-of-snca-in-rbd-and-progression-to-synucleinopathies/