|Title||Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Krohn, Lynne, Richard Y. J. Wu, Karl Heilbron, Jennifer A. Ruskey, Sandra B. Laurent, Cornelis Blauwendraat, Armaghan Alam, Isabelle Arnulf, Michele T. M. Hu, Yves Dauvilliers, Birgit Högl, Mathias Toft, Kari Anne Bjørnarå, Ambra Stefani, Evi Holzknecht, Christelle Charley Monaca, Beatriz Abril, Giuseppe Plazzi, Elena Antelmi, Luigi Ferini-Strambi, Peter Young, Anna Heidbreder, Valérie Cochen De Cock, Brit Mollenhauer, Friederike Sixel-Döring, Claudia Trenkwalder, Karel Sonka, David Kemlink, Michela Figorilli, Monica Puligheddu, Femke Dijkstra, Mineke Viaene, Wolfang Oertel, Marco Toffoli, Gian Luigi Gigli, Mariarosaria Valente, Jean-François Gagnon, Mike A. Nalls, Andrew B. Singleton, Alex Desautels, Jacques Y. Montplaisir, Paul Cannon, Owen A. Ross, Bradley F. Boeve, Nicolas Dupré, Edward A. Fon, Ronald B. Postuma, Lasse Pihlstrøm, Guy A. Rouleau, and Ziv Gan-Or|
|Corporate Authors||23andMe Research Team|
|Date Published||2020 04|
|Keywords||Adult, Aged, alpha-Synuclein, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Lewy Body Disease, Logistic Models, Male, Middle Aged, Odds Ratio, Parkinson Disease, Polymorphism, Single Nucleotide, Prodromal Symptoms, REM Sleep Behavior Disorder, Synucleinopathies|
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.
|Alternate Journal||Ann Neurol|