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

ObjectiveREM-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.\n\nMethodsFull sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n=1,076), Parkinsons 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.\n\nResultsA 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.\n\nInterpretationThere 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.