Journal
ANNALS OF NEUROLOGY
Volume 87, Issue 4, Pages 584-598Publisher
WILEY
DOI: 10.1002/ana.25687
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Funding
- Parkinson Society Canada
- Michael J. Fox Foundation
- Canadian Consortium on Neurodegeneration in Aging
- Canadian Glycomics Network
- Canada First Research Excellence Fund
- Hertie Foundation
- Fonds de recherche du Quebec-Sante Chercheur-Boursier award
- Mangurian Foundation Lewy Body Dementia Program
- Little Family Foundation
- American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center
- Mayo Clinic Lewy Body Dementia Association Research Center of Excellence
- APDA Center for Advanced Research
- MRC [MC_EX_MR/N50192X/1, MR/L023784/1, MR/M024962/1] Funding Source: UKRI
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Objective Rapid eye movement 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 disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). 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 (odds ratio [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. ANN NEUROL 2020
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