Dataset Information

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

ABSTRACT:

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;87:584-598.

SUBMITTER: Krohn L

PROVIDER: S-EPMC8025046 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

Krohn Lynne L Wu Richard Y J RYJ Heilbron Karl K Ruskey Jennifer A JA Laurent Sandra B SB Blauwendraat Cornelis C Alam Armaghan A Arnulf Isabelle I Hu Michele T M MTM Dauvilliers Yves Y Högl Birgit B Toft Mathias M Bjørnarå Kari Anne KA Stefani Ambra A Holzknecht Evi E Monaca Christelle Charley CC Abril Beatriz B Plazzi Giuseppe G Antelmi Elena E Ferini-Strambi Luigi L Young Peter P Heidbreder Anna A Cochen De Cock Valérie V Mollenhauer Brit B Sixel-Döring Friederike F Trenkwalder Claudia C Sonka Karel K Kemlink David D Figorilli Michela M Puligheddu Monica M Dijkstra Femke F Viaene Mineke M Oertel Wolfang W Toffoli Marco M Gigli Gian Luigi GL Valente Mariarosaria M Gagnon Jean-François JF Nalls Mike A MA Singleton Andrew B AB Desautels Alex A Montplaisir Jacques Y JY Cannon Paul P Ross Owen A OA Boeve Bradley F BF Dupré Nicolas N Fon Edward A EA Postuma Ronald B RB Pihlstrøm Lasse L Rouleau Guy A GA Gan-Or Ziv Z

Annals of neurology 20200212 4

<h4>Objective</h4>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.<h4>Methods</h4>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 diagno ...[more]

PMID: 31976583

Similar Datasets

Project description:ObjectiveTo localize the neuroanatomical substrate of rapid eye movement sleep behavior disorder (RBD) and to investigate the neuroanatomical locational relationship between RBD and α-synucleinopathy neurodegenerative diseases.Materials and methodsUsing a systematic PubMed search, we identified 19 patients with lesions in different brain regions that caused RBD. First, lesion network mapping was applied to confirm whether the lesion locations causing RBD corresponded to a common brain network. Second, the literature-based RBD lesion network map was validated using neuroimaging findings and locations of brain pathologies at post-mortem in patients with idiopathic RBD (iRBD) who were identified by independent systematic literature search using PubMed. Finally, we assessed the locational relationship between the sites of pathological alterations at the preclinical stage in α-synucleinopathy neurodegenerative diseases and the brain network for RBD.ResultsThe lesion network mapping showed lesions causing RBD to be localized to a common brain network defined by connectivity to the pons (including the locus coeruleus, dorsal raphe nucleus, central superior nucleus, and ventrolateral periaqueductal gray), regardless of the lesion location. The positive regions in the pons were replicated by the neuroimaging findings in an independent group of patients with iRBD and it coincided with the reported pathological alterations at post-mortem in patients with iRBD. Furthermore, all brain pathological sites at preclinical stages (Braak stages 1-2) in Parkinson's disease (PD) and at brainstem Lewy body disease in dementia with Lewy bodies (DLB) were involved in the brain network identified for RBD.ConclusionThe brain network defined by connectivity to positive pons regions might be the regulatory network loop inducing RBD in humans. In addition, our results suggested that the underlying cause of high phenoconversion rate from iRBD to neurodegenerative α-synucleinopathy might be pathological changes in the preclinical stage of α-synucleinopathy located at the regulatory network loop of RBD.

Dataset Information

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

Objective

Methods

Results

Interpretation

Publications

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

Similar Datasets

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