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Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.
Ann Neurol. 2020 04; 87(4):584-598.AN

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.

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Authors+Show Affiliations

Krohn L
Department of Human Genetics, McGill University, Montreal, Quebec, Canada. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Wu RYJ
Department of Human Genetics, McGill University, Montreal, Quebec, Canada. Department of Medicine, Imperial College London, London, United Kingdom.
Heilbron K
23andMe, Mountain View, CA.
Ruskey JA
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Laurent SB
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Blauwendraat C
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD.
Alam A
Department of Human Genetics, McGill University, Montreal, Quebec, Canada. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Arnulf I
Sleep Disorders Unit, Pitié-Salpêtrière Hospital, Institute for Brain and Spinal Cord, and Sorbonne University, Paris, France.
Hu MTM
Oxford Parkinson's Disease Center, University of Oxford, Oxford, United Kingdom. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Dauvilliers Y
National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui de Chauliac Hospital, University Hospital of Montpellier, University of Montpellier, Montpellier, France.
Högl B
Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Toft M
Department of Neurology, Oslo University Hospital, Oslo, Norway. Institue of Clinical Medicine, University of Oslo, Oslo, Norway.
Bjørnarå KA
Department of Neurology, Oslo University Hospital, Oslo, Norway.
Stefani A
Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Holzknecht E
Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Monaca CC
Department of Clinical Neurophysiology and Sleep Center, University Hospital of Lille, University of Lille North of France, Lille, France.
Abril B
Sleep Disorder Unit, Carémeau Hospital, University Hospital of Nîmes, Nîmes, France.
Plazzi G
Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy. Institute of Neurological Sciences, Scientific Institute for Research and Health Care, Bologna, Italy.
Antelmi E
Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy. Institute of Neurological Sciences, Scientific Institute for Research and Health Care, Bologna, Italy.
Ferini-Strambi L
Department of Neurological Sciences, Vita-Salute San Raffaele University, Milan, Italy.
Young P
Department of Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany.
Heidbreder A
Department of Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany.
Cochen De Cock V
Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France. EuroMov, University of Montpellier, Montpellier, France.
Mollenhauer B
Paracelsus Elena Clinic, Kassel, Germany. Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.
Sixel-Döring F
Paracelsus Elena Clinic, Kassel, Germany. Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.
Trenkwalder C
Paracelsus Elena Clinic, Kassel, Germany. Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.
Sonka K
Department of Neurology and Center of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
Kemlink D
Department of Neurology and Center of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
Figorilli M
Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
Puligheddu M
Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
Dijkstra F
Laboratory for Sleep Disorders, St Dimpna Regional Hospital, Geel, Belgium. Department of Neurology, St Dimpna Regional Hospital, Geel, Belgium.
Viaene M
Laboratory for Sleep Disorders, St Dimpna Regional Hospital, Geel, Belgium. Department of Neurology, St Dimpna Regional Hospital, Geel, Belgium.
Oertel W
Department of Neurology, Philipps University, Marburg, Germany.
Toffoli M
Department of Medicine, University of Udine, Udine, Italy. Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK.
Gigli GL
Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy. Department of Mathematics, Informatics, and Physics, University of Udine, Udine, Italy.
Valente M
Department of Medicine, University of Udine, Udine, Italy. Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.
Gagnon JF
Center for Advanced Studies in Sleep Medicine, Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada. Department of Psychology, Université du Québec à Montréal, Montréal, QC, Canada.
Nalls MA
Data Tecnica International, Glen Echo, MD.
Singleton AB
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD.
23andMe Research Team
23andMe, Mountain View, CA.
Desautels A
Center for Advanced Studies in Sleep Medicine, Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada. Department of Neurosciences, University of Montreal, Montreal, Quebec, Canada.
Montplaisir JY
Center for Advanced Studies in Sleep Medicine, Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada. Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada.
Cannon P
23andMe, Mountain View, CA.
Ross OA
Departments of Neuroscience and Clinical Genomics, Mayo Clinic, Jacksonville, FL.
Boeve BF
Department of Neurology, Mayo Clinic, Rochester, MN.
Dupré N
Division of Neurosciences, University Hospital of Quebec, Laval University, Quebec City, Quebec, Canada. Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
Fon EA
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Postuma RB
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. Center for Advanced Studies in Sleep Medicine, Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
Pihlstrøm L
Department of Neurology, Oslo University Hospital, Oslo, Norway.
Rouleau GA
Department of Human Genetics, McGill University, Montreal, Quebec, Canada. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Gan-Or Z
Department of Human Genetics, McGill University, Montreal, Quebec, Canada. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

MeSH

AdultAgedCase-Control StudiesFemaleGenetic Predisposition to DiseaseHumansLewy Body DiseaseLogistic ModelsMaleMiddle AgedOdds RatioParkinson DiseasePolymorphism, Single NucleotideProdromal SymptomsREM Sleep Behavior DisorderSynucleinopathiesalpha-Synuclein

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31976583

Citation

Krohn, Lynne, et al. "Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies." Annals of Neurology, vol. 87, no. 4, 2020, pp. 584-598.
Krohn L, Wu RYJ, Heilbron K, et al. Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies. Ann Neurol. 2020;87(4):584-598.
Krohn, L., Wu, R. Y. J., Heilbron, K., Ruskey, J. A., Laurent, S. B., Blauwendraat, C., Alam, A., Arnulf, I., Hu, M. T. M., Dauvilliers, Y., Högl, B., Toft, M., Bjørnarå, K. A., Stefani, A., Holzknecht, E., Monaca, C. C., Abril, B., Plazzi, G., Antelmi, E., ... Gan-Or, Z. (2020). Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies. Annals of Neurology, 87(4), 584-598. https://doi.org/10.1002/ana.25687
Krohn L, et al. Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies. Ann Neurol. 2020;87(4):584-598. PubMed PMID: 31976583.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies. 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 - ,, 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, Y1 - 2020/02/12/ PY - 2019/09/03/received PY - 2020/01/20/revised PY - 2020/01/20/accepted PY - 2020/1/25/pubmed PY - 2020/7/28/medline PY - 2020/1/25/entrez SP - 584 EP - 598 JF - Annals of neurology JO - Ann Neurol VL - 87 IS - 4 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. SN - 1531-8249 UR - https://www.unboundmedicine.com/medline/citation/31976583/Fine_Mapping_of_SNCA_in_Rapid_Eye_Movement_Sleep_Behavior_Disorder_and_Overt_Synucleinopathies_ L2 - https://doi.org/10.1002/ana.25687 DB - PRIME DP - Unbound Medicine ER -