@article{91de3bf0f21e44b7a17cf9bc0da6554e,
title = "Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies: Annals of Neurology",
abstract = "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. {\textcopyright} 2020 American Neurological Association",
keywords = "synuclein, aged, Article, behavior disorder, case control study, cohort analysis, controlled study, diffuse Lewy body disease, disease duration, female, gene frequency, gene linkage disequilibrium, gene locus, gene mapping, gene replication, gene sequence, genetic variability, genotype, human, major clinical study, male, nerve degeneration, Parkinson disease, priority journal, REM sleep, single nucleotide polymorphism, synucleinopathy",
author = "L. Krohn and R.Y.J. Wu and K. Heilbron and J.A. Ruskey and S.B. Laurent and C. Blauwendraat and A. Alam and I. Arnulf and M.T.M. Hu and Y. Dauvilliers and B. H{\"o}gl and M. Toft and K.A. Bj{\o}rnar{\aa} and A. Stefani and E. Holzknecht and C.C. Monaca and B. Abril and G. Plazzi and E. Antelmi and L. Ferini-Strambi and P. Young and A. Heidbreder and {Cochen De Cock}, V. and B. Mollenhauer and F. Sixel-D{\"o}ring and C. Trenkwalder and K. Sonka and D. Kemlink and M. Figorilli and M. Puligheddu and F. Dijkstra and M. Viaene and W. Oertel and M. Toffoli and G.L. Gigli and M. Valente and J.-F. Gagnon and M.A. Nalls and A.B. Singleton and A. Desautels and J.Y. Montplaisir and P. Cannon and O.A. Ross and B.F. Boeve and N. Dupr{\'e} and E.A. Fon and R.B. Postuma and L. Pihlstr{\o}m and G.A. Rouleau and Z. Gan-Or and Team, {23andMe Research}",
note = "Cited By :7 Export Date: 11 March 2021 CODEN: ANNED Correspondence Address: Gan-Or, Z.; Department of Human Genetics, Canada; email: ziv.gan-or@mcgill.ca Funding details: Michael J. Fox Foundation for Parkinson's Research, MJFF Funding details: Mayo Clinic Funding details: American Parkinson Disease Association, APDA Funding details: McGill University Funding details: Little Family Foundation Funding details: Consortium canadien en neurod{\'e}g{\'e}n{\'e}rescence associ{\'e}e au vieillissement, CCNA Funding details: Lewy Body Dementia Association, LBDA Funding details: Fonds de Recherche du Qu{\'e}bec - Sant{\'e}, FRQS Funding details: Parkinson Society Canada, PSC Funding details: Canadian Glycomics Network, GlycoNet Funding details: Parkinson Canada Funding text 1: We thank the patients and control subjects for their participation in this study; the Quebec Parkinson's Network ( http://rpq-qpn.ca/en/ ) for access to some of the participants for this research; and D. Rochefort, H. Catoire, and V. Zaharieva for their assistance. Mayo Clinic is supported in part by the Mangurian Foundation Lewy Body Dementia Program, the Little Family Foundation, an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and the Mayo Clinic Lewy Body Dementia Association Research Center of Excellence. Funding text 2: This work was supported by Parkinson Society Canada, the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging, the Canadian Glycomics Network, and the Canada First Research Excellence Fund, with funds awarded to McGill University for the Healthy Brains for Healthy Lives program. J.F.G. holds a Canada Research Chair in Cognitive Decline in Pathological Aging. G.A.R. holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences. W.O. is Hertie Senior Research Professor, supported by the Hertie Foundation. E.A.F. holds a Canada Research Chair (Tier 1) in Parkinson disease. Z.G.O. is supported by the Fonds de recherche du Qu{\'e}bec–Sant{\'e} Chercheur‐Boursier award and is a Parkinson Canada New Investigator awardee. Funding text 3: This work was supported by Parkinson Society Canada, the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging, the Canadian Glycomics Network, and the Canada First Research Excellence Fund, with funds awarded to McGill University for the Healthy Brains for Healthy Lives program. J.F.G. holds a Canada Research Chair in Cognitive Decline in Pathological Aging. G.A.R. holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences. W.O. is Hertie Senior Research Professor, supported by the Hertie Foundation. E.A.F. holds a Canada Research Chair (Tier 1) in Parkinson disease. Z.G.O. is supported by the Fonds de recherche du Qu?bec?Sant? Chercheur-Boursier award and is a Parkinson Canada New Investigator awardee. We thank the patients and control subjects for their participation in this study; the Quebec Parkinson's Network (http://rpq-qpn.ca/en/) for access to some of the participants for this research; and D. Rochefort, H. Catoire, and V. Zaharieva for their assistance. Mayo Clinic is supported in part by the Mangurian Foundation Lewy Body Dementia Program, the Little Family Foundation, an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and the Mayo Clinic Lewy Body Dementia Association Research Center of Excellence.",
year = "2020",
doi = "10.1002/ana.25687",
language = "English",
volume = "87",
pages = "584--598",
journal = "Ann. Neurol.",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "4",
}