Fine-mapping of SNCA in REM sleep behavior disorder and overt synucleinopathies

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Abstract Objective REM-sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n=1,076), Parkinson’s disease (PD, n=1,013), and dementia with Lewy bodies (DLB, n=415), and in control subjects (n=6,155). A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (cases n=1,782, controls n=131,250). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis. Results A 5’-region SNCA variant (rs10005233) was associated with iRBD (OR=1.43, p =1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5’ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3’ of SNCA (OR=1.32, p =4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR=5.74, p =2E-06). The known top PD-associated variant (3’ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3’ of SNCA . Several 5’ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies, and may suggest a cognitive component to this region.

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