TY - JOUR
T1 - Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies
AU - 23andMe Research Team
AU - Krohn, Lynne
AU - Wu, Richard Y.J.
AU - Heilbron, Karl
AU - Ruskey, Jennifer A.
AU - Laurent, Sandra B.
AU - Blauwendraat, Cornelis
AU - Alam, Armaghan
AU - Arnulf, Isabelle
AU - Hu, Michele T.M.
AU - Dauvilliers, Yves
AU - Högl, Birgit
AU - Toft, Mathias
AU - Bjørnarå, Kari Anne
AU - Stefani, Ambra
AU - Holzknecht, Evi
AU - Monaca, Christelle Charley
AU - Abril, Beatriz
AU - Plazzi, Giuseppe
AU - Antelmi, Elena
AU - Ferini-Strambi, Luigi
AU - Young, Peter
AU - Heidbreder, Anna
AU - Cochen De Cock, Valérie
AU - Mollenhauer, Brit
AU - Sixel-Döring, Friederike
AU - Trenkwalder, Claudia
AU - Sonka, Karel
AU - Kemlink, David
AU - Figorilli, Michela
AU - Puligheddu, Monica
AU - Dijkstra, Femke
AU - Viaene, Mineke
AU - Oertel, Wolfang
AU - Toffoli, Marco
AU - Gigli, Gian Luigi
AU - Valente, Mariarosaria
AU - Gagnon, Jean François
AU - Nalls, Mike A.
AU - Singleton, Andrew B.
AU - Desautels, Alex
AU - Montplaisir, Jacques Y.
AU - Cannon, Paul
AU - Ross, Owen A.
AU - Boeve, Bradley F.
AU - Dupré, Nicolas
AU - Fon, Edward A.
AU - Postuma, Ronald B.
AU - Pihlstrøm, Lasse
AU - Rouleau, Guy A.
AU - Gan-Or, Ziv
N1 - Publisher Copyright:
© 2020 American Neurological Association
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
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U2 - 10.1002/ana.25687
DO - 10.1002/ana.25687
M3 - Article
AN - SCOPUS:85079453924
SN - 0364-5134
VL - 87
SP - 584
EP - 598
JO - Annals of neurology
JF - Annals of neurology
IS - 4
ER -