Lynne Krohn1,2, Richard Y J Wu1,3, Karl Heilbron4, Jennifer A Ruskey2,5, Sandra B Laurent2,5, Cornelis Blauwendraat6, Armaghan Alam1,2, Isabelle Arnulf7, Michele T M Hu8,9, Yves Dauvilliers10, Birgit Högl11, Mathias Toft12,13, Kari Anne Bjørnarå12, Ambra Stefani11, Evi Holzknecht11, Christelle Charley Monaca14, Beatriz Abril15, Giuseppe Plazzi16,17, Elena Antelmi16,17, Luigi Ferini-Strambi18, Peter Young19, Anna Heidbreder19, Valérie Cochen De Cock20,21, Brit Mollenhauer22,23, Friederike Sixel-Döring22,23, Claudia Trenkwalder22,23, Karel Sonka24, David Kemlink24, Michela Figorilli25, Monica Puligheddu25, Femke Dijkstra26,27, Mineke Viaene26,27, Wolfang Oertel28, Marco Toffoli29,30, Gian Luigi Gigli31,32, Mariarosaria Valente29,31, Jean-François Gagnon33,34, Mike A Nalls35, Andrew B Singleton6, Alex Desautels33,36, Jacques Y Montplaisir33,37, Paul Cannon4, Owen A Ross38, Bradley F Boeve39, Nicolas Dupré40,41, Edward A Fon2,5, Ronald B Postuma2,5,33, Lasse Pihlstrøm12, Guy A Rouleau1,2,5, Ziv Gan-Or1,2,5. 1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. 2. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. 3. Department of Medicine, Imperial College London, London, United Kingdom. 4. 23andMe, Mountain View, CA. 5. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. 6. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD. 7. Sleep Disorders Unit, Pitié-Salpêtrière Hospital, Institute for Brain and Spinal Cord, and Sorbonne University, Paris, France. 8. Oxford Parkinson's Disease Center, University of Oxford, Oxford, United Kingdom. 9. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom. 10. National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui de Chauliac Hospital, University Hospital of Montpellier, University of Montpellier, Montpellier, France. 11. Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. 12. Department of Neurology, Oslo University Hospital, Oslo, Norway. 13. Institue of Clinical Medicine, University of Oslo, Oslo, Norway. 14. Department of Clinical Neurophysiology and Sleep Center, University Hospital of Lille, University of Lille North of France, Lille, France. 15. Sleep Disorder Unit, Carémeau Hospital, University Hospital of Nîmes, Nîmes, France. 16. Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy. 17. Institute of Neurological Sciences, Scientific Institute for Research and Health Care, Bologna, Italy. 18. Department of Neurological Sciences, Vita-Salute San Raffaele University, Milan, Italy. 19. Department of Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany. 20. Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France. 21. EuroMov, University of Montpellier, Montpellier, France. 22. Paracelsus Elena Clinic, Kassel, Germany. 23. Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany. 24. Department of Neurology and Center of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic. 25. Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy. 26. Laboratory for Sleep Disorders, St Dimpna Regional Hospital, Geel, Belgium. 27. Department of Neurology, St Dimpna Regional Hospital, Geel, Belgium. 28. Department of Neurology, Philipps University, Marburg, Germany. 29. Department of Medicine, University of Udine, Udine, Italy. 30. Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK. 31. Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy. 32. Department of Mathematics, Informatics, and Physics, University of Udine, Udine, Italy. 33. Center for Advanced Studies in Sleep Medicine, Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada. 34. Department of Psychology, Université du Québec à Montréal, Montréal, QC, Canada. 35. Data Tecnica International, Glen Echo, MD. 36. Department of Neurosciences, University of Montreal, Montreal, Quebec, Canada. 37. Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada. 38. Departments of Neuroscience and Clinical Genomics, Mayo Clinic, Jacksonville, FL. 39. Department of Neurology, Mayo Clinic, Rochester, MN. 40. Division of Neurosciences, University Hospital of Quebec, Laval University, Quebec City, Quebec, Canada. 41. Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
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.
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.
Authors: Lasse Pihlstrøm; Cornelis Blauwendraat; Chiara Cappelletti; Victoria Berge-Seidl; Margrete Langmyhr; Sandra Pilar Henriksen; Wilma D J van de Berg; J Raphael Gibbs; Mark R Cookson; Andrew B Singleton; Mike A Nalls; Mathias Toft Journal: Ann Neurol Date: 2018-08-26 Impact factor: 10.422
Authors: Z Gan-Or; N Giladi; U Rozovski; C Shifrin; S Rosner; T Gurevich; A Bar-Shira; A Orr-Urtreger Journal: Neurology Date: 2008-04-23 Impact factor: 9.910
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Authors: Anna Sailer; Sonja W Scholz; Michael A Nalls; Claudia Schulte; Monica Federoff; T Ryan Price; Andrew Lees; Owen A Ross; Dennis W Dickson; Kin Mok; Niccolo E Mencacci; Lucia Schottlaender; Viorica Chelban; Helen Ling; Sean S O'Sullivan; Nicholas W Wood; Bryan J Traynor; Luigi Ferrucci; Howard J Federoff; Timothy R Mhyre; Huw R Morris; Günther Deuschl; Niall Quinn; Hakan Widner; Alberto Albanese; Jon Infante; Kailash P Bhatia; Werner Poewe; Wolfgang Oertel; Günter U Höglinger; Ullrich Wüllner; Stefano Goldwurm; Maria Teresa Pellecchia; Joaquim Ferreira; Eduardo Tolosa; Bastiaan R Bloem; Olivier Rascol; Wassilios G Meissner; John A Hardy; Tamas Revesz; Janice L Holton; Thomas Gasser; Gregor K Wenning; Andrew B Singleton; Henry Houlden Journal: Neurology Date: 2016-09-14 Impact factor: 9.910
Authors: Uladzislau Rudakou; Eric Yu; Lynne Krohn; Jennifer A Ruskey; Farnaz Asayesh; Yves Dauvilliers; Dan Spiegelman; Lior Greenbaum; Stanley Fahn; Cheryl H Waters; Nicolas Dupré; Guy A Rouleau; Sharon Hassin-Baer; Edward A Fon; Roy N Alcalay; Ziv Gan-Or Journal: Brain Date: 2021-03-03 Impact factor: 13.501
Authors: Jason W Adams; Michael L Alosco; Jesse Mez; Victor E Alvarez; Bertrand R Huber; Yorghos Tripodis; Charles H Adler; Carol Kubilius; Kerry A Cormier; Rebecca Mathais; Raymond Nicks; Hunter J Kelley; Nicole Saltiel; Madeline Uretsky; Evan Nair; Nurgul Aytan; Jonathan D Cherry; Christopher J Nowinski; Neil W Kowall; Lee E Goldstein; Brigid Dwyer; Douglas I Katz; Robert C Cantu; Robert A Stern; Ann C McKee; Thor D Stein Journal: Acta Neuropathol Date: 2020-09-17 Impact factor: 17.088
Authors: Mitchell G Miglis; Charles H Adler; Elena Antelmi; Dario Arnaldi; Luca Baldelli; Bradley F Boeve; Matteo Cesari; Irene Dall'Antonia; Nico J Diederich; Kathrin Doppler; Petr Dušek; Raffaele Ferri; Jean-François Gagnon; Ziv Gan-Or; Wiebke Hermann; Birgit Högl; Michele T Hu; Alex Iranzo; Annette Janzen; Anastasia Kuzkina; Jee-Young Lee; Klaus L Leenders; Simon J G Lewis; Claudio Liguori; Jun Liu; Christine Lo; Kaylena A Ehgoetz Martens; Jiri Nepozitek; Giuseppe Plazzi; Federica Provini; Monica Puligheddu; Michal Rolinski; Jan Rusz; Ambra Stefani; Rebekah L S Summers; Dallah Yoo; Jennifer Zitser; Wolfgang H Oertel Journal: Lancet Neurol Date: 2021-08 Impact factor: 44.182
Authors: Luis M A Oliveira; Thomas Gasser; Robert Edwards; Markus Zweckstetter; Ronald Melki; Leonidas Stefanis; Hilal A Lashuel; David Sulzer; Kostas Vekrellis; Glenda M Halliday; Julianna J Tomlinson; Michael Schlossmacher; Poul Henning Jensen; Julia Schulze-Hentrich; Olaf Riess; Warren D Hirst; Omar El-Agnaf; Brit Mollenhauer; Peter Lansbury; Tiago F Outeiro Journal: NPJ Parkinsons Dis Date: 2021-07-26
Authors: Kheireddin Mufti; Eric Yu; Uladzislau Rudakou; Lynne Krohn; Jennifer A Ruskey; Farnaz Asayesh; Sandra B Laurent; Dan Spiegelman; Isabelle Arnulf; Michele T M Hu; Jacques Y Montplaisir; Jean-François Gagnon; Alex Desautels; Yves Dauvilliers; Gian Luigi Gigli; Mariarosaria Valente; Francesco Janes; Andrea Bernardini; Birgit Högl; Ambra Stefani; Evi Holzknecht; Karel Sonka; David Kemlink; Wolfgang Oertel; Annette Janzen; Giuseppe Plazzi; Elena Antelmi; Michela Figorilli; Monica Puligheddu; Brit Mollenhauer; Claudia Trenkwalder; Friederike Sixel-Döring; Valérie Cochen De Cock; Christelle Charley Monaca; Anna Heidbreder; Luigi Ferini-Strambi; Femke Dijkstra; Mineke Viaene; Beatriz Abril; Bradley F Boeve; Jean-François Trempe; Guy A Rouleau; Ronald B Postuma; Ziv Gan-Or Journal: Neurology Date: 2021-01-04 Impact factor: 9.910