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

Krohn, L. M.; Wu, R. Y.; Heilbron, K.; Ruskey, J. A.; Laurent, S. B.; Blauwendraat, C.; Alam, A.; Arnulf, I.; Hu, M. T.; Dauvilliers, Y.; Högl, B.; Toft, M.; Bjornara, K. A.; Stefani, A.; Holzknecht, E.; Monaca, C. C.; Beatriz, A.; Plazzi, G.; Antelmi, E.; Ferini-Strambi, L.; Young, P.; Heidbreder, A.; Cochen De Cock, V.; Mollenhauer, B.; Sixel-Döring, F.; Trenkwalder, C.; Sonka, K.; Kemlink, D.; Figorilli, M.; Puligheddu, M.; Dijkstra, F.; Viaene, M.; Oertel, W.; Toffoli, M.; Gigli, G. L.; Valente, M.; Gagnon, J.-F.; Nalls, M. A.; Singleton, A. B.; 23andMe Research Team,; Desautels, A.; M

doi:10.1101/756528

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bioRxiv · 10.1101/756528

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

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Abstract

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.

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Krohn, L. M., Wu, R. Y., Heilbron, K., Ruskey, J. A., Laurent, S. B., Blauwendraat, C., Alam, A., Arnulf, I., Hu, M. T., Dauvilliers, Y., Högl, B., Toft, M., Bjornara, K. A., Stefani, A., Holzknecht, E., Monaca, C. C., Beatriz, A., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Young, P., Heidbreder, A., Cochen De Cock, V., Mollenhauer, B., Sixel-Döring, F., Trenkwalder, C., Sonka, K., Kemlink, D., Figorilli, M., Puligheddu, M., Dijkstra, F., Viaene, M., Oertel, W., Toffoli, M., Gigli, G. L., Valente, M., Gagnon, J.-F., Nalls, M. A., Singleton, A. B., 23andMe Research Team,, Desautels, A., M. 2019-09-04. Fine-mapping of SNCA in REM sleep behavior disorder and overt synucleinopathies. https://doi.org/10.1101/756528

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