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

Lynne Krohn 1, 2 Richard Wu 1, 3 Karl Heilbron 4 Jennifer Ruskey 2 Sandra Laurent 2 Cornelis Blauwendraat 5 Armaghan Alam 6, 2 Isabelle Arnulf 7 Michele Hu 8, 9 Yves Dauvilliers 10 Birgit Högl 11 Mathias Toft 12 Kari Anne Bjørnarå 12 Ambra Stefani 11 Evi Holzknecht 11 Christelle Charley Monaca 13 Beatriz Abril 14 Giuseppe Plazzi 15, 16 Elena Antelmi 15, 17 Luigi Ferini-Strambi 18 Peter Young 19 Anna Heidbreder 19 Valérie Cochen de Cock 20, 21 Brit Mollenhauer 22, 23 Friederike Sixel-Döring 22, 23 Claudia Trenkwalder 22, 23 Karel Sonka 24 David Kemlink 24 Michela Figorilli 25 Monica Puligheddu 25 Femke Dijkstra 26 Mineke Viaene 26 Wolfang Oertel 27 Marco Toffoli 28, 29 Gian Luigi Gigli 30 Mariarosaria Valente 28 Jean-François Gagnon 31, 32 Mike Nalls 33 Andrew Singleton 5 Alex Desautels 34, 32 Jacques Montplaisir 34, 32 Paul Cannon 4 Owen Ross 35 Bradley Boeve 36 Nicolas Dupré 37 Edward Fon 2 Ronald Postuma 2, 34 Lasse Pihlstrøm 12 Guy Rouleau 1, 2 Ziv Gan-Or 1, 2 
Abstract : 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.
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https://hal.umontpellier.fr/hal-03481669
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Soumis le : mercredi 15 décembre 2021 - 14:25:48
Dernière modification le : mercredi 5 octobre 2022 - 09:02:05

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Lynne Krohn, Richard Wu, Karl Heilbron, Jennifer Ruskey, Sandra Laurent, et al.. Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies. Annals of Neurology, Wiley, 2020, 87 (4), pp.584-598. ⟨10.1002/ana.25687⟩. ⟨hal-03481669⟩

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