Fine-mapping of SNCA in REM sleep behavior disorder and overt synucleinopathies
| Autor: | Michele T.M. Hu, Armaghan Alam, Lynne Krohn, Guy A. Rouleau, Richard Y.J. Wu, Cornelis Blauwendraat, Jacques Montplaisir, Ambra Stefani, Mike A. Nalls, Karl Heilbron, Luigi Ferini-Strambi, Paul Cannon, C. Trenkwalder, Kari Anne Bjørnarå, Sandra B. Laurent, Edward A. Fon, Femke Dijkstra, Christelle Charley Monaca, Peter Young, Mineke Viaene, Birgit Högl, Nicolas Dupré, Monica Puligheddu, Bradley F. Boeve, W. H. Oertel, Jennifer A. Ruskey, Karel Sonka, Ziv Gan-Or, Abril Beatriz, Anna Heidbreder, David Kemlink, Andrew B. Singleton, Owen A. Ross, Evi Holzknecht, Gian Luigi Gigli, Marco Toffoli, Friederike Sixel-Döring, Mathias Toft, Mariarosaria Valente, Alex Desautels, Valérie Cochen De Cock, Yves Dauvilliers, Elena Antelmi, Lasse Pihlstrøm, Jean-François Gagnon, Michela Figorilli, Isabelle Arnulf, Ronald B. Postuma, Brit Mollenhauer, Giuseppe Plazzi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Synucleinopathies
Genetics 0303 health sciences Linkage disequilibrium Dementia with Lewy bodies business.industry Locus (genetics) Single-nucleotide polymorphism medicine.disease REM sleep behavior disorder 3. Good health 03 medical and health sciences symbols.namesake 0302 clinical medicine Bonferroni correction symbols medicine business 030217 neurology & neurosurgery Survival analysis 030304 developmental biology |
| DOI: | 10.1101/756528 |
| Popis: | ObjectiveREM-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.MethodsFull sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n=1,076), Parkinson’s disease (PD, n=1,013), and dementia with Lewy bodies (DLB, n=415), and in control subjects (n=6,155). A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (cases n=1,782, controls n=131,250). 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.ResultsA 5’-region SNCA variant (rs10005233) was associated with iRBD (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.InterpretationThere 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, and may suggest a cognitive component to this region. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|