Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies
2 Montreal Neurological Institute and Hospital
3 Imperial College London
4 23andMe Inc.
5 NIA - National Institute on Aging [Bethesda, USA]
6 McGill University = Université McGill [Montréal, Canada]
7 CIC Neurosciences - Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière]
8 University of Oxford
9 Nuffield Department of Clinical Neurosciences [Oxford]
10 Département de neurologie [Montpellier]
11 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
12 Oslo University Hospital [Oslo]
13 CHRU Lille - Service de neurophysiologie clinique
14 CHU Nîmes - Hôpital Universitaire Carémeau [Nîmes]
15 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna [Bologne]
16 Department of Biomedical and Neuromotor Sciences [Bologna, Italy]
17 UniSR - Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie]
18 WWU - Westfälische Wilhelms-Universität Münster = University of Münster = Université de Münster [Münster, Allemagne]
19 Clinique Beau Soleil [Montpellier]
20 EuroMov - Euromov
21 Paracelsus-Elena-Klinik, Kassel, Germany.
22 UMG - University Medical Center Göttingen
23 1. LF UK / 1st Faculty of Medicine - 1. lékařská fakulta, Univerzita Karlova [Praha, Česká republika] = First Faculty of Medicine, Charles University [Prague, Czech Republic]
24 UniCa - Università degli Studi di Cagliari = University of Cagliari = Université de Cagliari
25 Algemeen Ziekenhuis Sint-Dimpna
26 Philipps Universität Marburg = Philipps University of Marburg
27 Università degli Studi di Udine - University of Udine [Italie]
28 UCL - University College London [UCL]
29 Department of Mathematics and Computer Science [Udine]
30 Hôpital du Sacré-Coeur de Montréal
31 UQAM - Université du Québec à Montréal = University of Québec in Montréal
32 Data Tecnica International
33 CEAMS - Centre d'études avancées en Médecine du Sommeil
34 Mayo Clinic [Jacksonville]
35 Mayo Clinic [Rochester]
36 Laval University Medical center
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Résumé
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.