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Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies
Author(s) -
Krohn Lynne,
Wu Richard Y. J.,
Heilbron Karl,
Ruskey Jennifer A.,
Laurent Sandra B.,
Blauwendraat Cornelis,
Alam Armaghan,
Arnulf Isabelle,
Hu Michele T. M.,
Dauvilliers Yves,
Högl Birgit,
Toft Mathias,
Bjørnarå Kari Anne,
Stefani Ambra,
Holzknecht Evi,
Monaca Christelle Charley,
Abril Beatriz,
Plazzi Giuseppe,
Antelmi Elena,
FeriniStrambi Luigi,
Young Peter,
Heidbreder Anna,
Cochen De Cock Valérie,
Mollenhauer Brit,
SixelDöring Friederike,
Trenkwalder Claudia,
Sonka Karel,
Kemlink David,
Figorilli Michela,
Puligheddu Monica,
Dijkstra Femke,
Viaene Mineke,
Oertel Wolfang,
Toffoli Marco,
Gigli Gian Luigi,
Valente Mariarosaria,
Gag JeanFrançois,
Nalls Mike A.,
Singleton Andrew B.,
Desautels Alex,
Montplaisir Jacques Y.,
Can Paul,
Ross Owen A.,
Boeve Bradley F.,
Dupré Nicolas,
Fon Edward A.,
Postuma Ronald B.,
Pihlstrøm Lasse,
Rouleau Guy A.,
GanOr Ziv
Publication year - 2020
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25687
Subject(s) - synucleinopathies , rem sleep behavior disorder , rapid eye movement sleep , dementia with lewy bodies , parkinson's disease , odds ratio , logistic regression , medicine , oncology , psychology , alpha synuclein , dementia , disease , neuroscience , eye movement
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