ParkinsonCanadaV1, Pmc, Corpus, bibRecord, 000052

GBA mutations are associated with Rapid Eye Movement Sleep Behavior Disorder

Identifieur interne : 000052 ( Pmc/Corpus ); précédent : 000051; suivant : 000053

GBA mutations are associated with Rapid Eye Movement Sleep Behavior Disorder

Auteurs : Ziv Gan-Or ; Anat Mirelman ; Ronald B. Postuma ; Isabelle Arnulf ; Anat Bar-Shira ; Yves Dauvilliers ; Alex Desautels ; Jean-François Gagnon ; Claire S. Leblond ; Birgit Frauscher ; Roy N. Alcalay ; Rachel Saunders-Pullman ; Susan B. Bressman ; Karen Marder ; Christelle Monaca ; Birgit Högl ; Avi Orr-Urtreger ; Patrick A. Dion ; Jacques Y. Montplaisir ; Nir Giladi ; Guy A. Rouleau

Source :

Annals of Clinical and Translational Neurology [ 2328-9503 ] ; 2015.

RBID : PMC:4574811

Abstract

Rapid eye movement sleep behavior disorder and GBA mutations are both associated with Parkinson's disease. The GBA gene was sequenced in idiopathic rapid eye movement sleep behavior disorder patients (n = 265), and compared to controls (n = 2240). Rapid eye movement sleep behavior disorder questionnaire was performed in an independent Parkinson's disease cohort (n = 120). GBA mutations carriers had an OR of 6.24 (10.2% in patients vs. 1.8% in controls, P < 0.0001) for rapid eye movement sleep behavior disorder, and among Parkinson's disease patients, the OR for mutation carriers to have probable rapid eye movement sleep behavior disorder was 3.13 (P = 0.039). These results demonstrate that rapid eye movement sleep behavior disorder is associated with GBA mutations, and that combining genetic and prodromal data may assist in identifying individuals susceptible to Parkinson's disease.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574811

DOI: 10.1002/acn3.228
PubMed: 26401515
PubMed Central: 4574811

Links to Exploration step

PMC:4574811

Le document en format XML

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<author><name sortKey="Gan Or, Ziv" sort="Gan Or, Ziv" uniqKey="Gan Or Z" first="Ziv" last="Gan-Or">Ziv Gan-Or</name>
<affiliation><nlm:aff id="au1"><institution>Montreal Neurological Institute, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au2"><institution>Department of Human Genetics, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
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<author><name sortKey="Mirelman, Anat" sort="Mirelman, Anat" uniqKey="Mirelman A" first="Anat" last="Mirelman">Anat Mirelman</name>
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<addr-line>Tel-Aviv, Israel</addr-line>
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<author><name sortKey="Postuma, Ronald B" sort="Postuma, Ronald B" uniqKey="Postuma R" first="Ronald B" last="Postuma">Ronald B. Postuma</name>
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<author><name sortKey="Arnulf, Isabelle" sort="Arnulf, Isabelle" uniqKey="Arnulf I" first="Isabelle" last="Arnulf">Isabelle Arnulf</name>
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<addr-line>Paris, France</addr-line>
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<author><name sortKey="Bar Shira, Anat" sort="Bar Shira, Anat" uniqKey="Bar Shira A" first="Anat" last="Bar-Shira">Anat Bar-Shira</name>
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<addr-line>Tel-Aviv, Israel</addr-line>
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<author><name sortKey="Dauvilliers, Yves" sort="Dauvilliers, Yves" uniqKey="Dauvilliers Y" first="Yves" last="Dauvilliers">Yves Dauvilliers</name>
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<addr-line>Montréal, Quebec, Canada</addr-line>
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<affiliation><nlm:aff id="au9"><institution>Department of Neurosciences, Université de Montréal</institution>
<addr-line>Montréal, Canada</addr-line>
</nlm:aff>
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<author><name sortKey="Gagnon, Jean Francois" sort="Gagnon, Jean Francois" uniqKey="Gagnon J" first="Jean-François" last="Gagnon">Jean-François Gagnon</name>
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<addr-line>Montréal, Quebec, Canada</addr-line>
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<affiliation><nlm:aff id="au10"><institution>Département de psychologie, Université du Québec à Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
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<author><name sortKey="Leblond, Claire S" sort="Leblond, Claire S" uniqKey="Leblond C" first="Claire S" last="Leblond">Claire S. Leblond</name>
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<affiliation><nlm:aff id="au2"><institution>Department of Human Genetics, McGill University</institution>
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<author><name sortKey="Frauscher, Birgit" sort="Frauscher, Birgit" uniqKey="Frauscher B" first="Birgit" last="Frauscher">Birgit Frauscher</name>
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<addr-line>Innsbruck, Austria</addr-line>
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<author><name sortKey="Alcalay, Roy N" sort="Alcalay, Roy N" uniqKey="Alcalay R" first="Roy N" last="Alcalay">Roy N. Alcalay</name>
<affiliation><nlm:aff id="au12"><institution>Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University</institution>
<addr-line>New York, New York</addr-line>
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<author><name sortKey="Saunders Pullman, Rachel" sort="Saunders Pullman, Rachel" uniqKey="Saunders Pullman R" first="Rachel" last="Saunders-Pullman">Rachel Saunders-Pullman</name>
<affiliation><nlm:aff id="au13"><institution>Department of Neurology, Icahn School of Medicine at Mount Sinai</institution>
<addr-line>New York, New York</addr-line>
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</affiliation>
<affiliation><nlm:aff id="au14"><institution>Department of Neurology, Albert Einstein College of Medicine Bronx</institution>
<addr-line>New York, New York</addr-line>
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<author><name sortKey="Bressman, Susan B" sort="Bressman, Susan B" uniqKey="Bressman S" first="Susan B" last="Bressman">Susan B. Bressman</name>
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<addr-line>New York, New York</addr-line>
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<author><name sortKey="Marder, Karen" sort="Marder, Karen" uniqKey="Marder K" first="Karen" last="Marder">Karen Marder</name>
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<addr-line>New York, New York</addr-line>
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<author><name sortKey="Monaca, Christelle" sort="Monaca, Christelle" uniqKey="Monaca C" first="Christelle" last="Monaca">Christelle Monaca</name>
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<addr-line>Lille, France</addr-line>
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</affiliation>
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<author><name sortKey="Hogl, Birgit" sort="Hogl, Birgit" uniqKey="Hogl B" first="Birgit" last="Högl">Birgit Högl</name>
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<author><name sortKey="Orr Urtreger, Avi" sort="Orr Urtreger, Avi" uniqKey="Orr Urtreger A" first="Avi" last="Orr-Urtreger">Avi Orr-Urtreger</name>
<affiliation><nlm:aff id="au6"><institution>The Genetic Institute, Tel-Aviv Sourasky Medical Center</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au18"><institution>The Sackler Faculty of Medicine, Tel-Aviv University</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
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<author><name sortKey="Dion, Patrick A" sort="Dion, Patrick A" uniqKey="Dion P" first="Patrick A" last="Dion">Patrick A. Dion</name>
<affiliation><nlm:aff id="au1"><institution>Montreal Neurological Institute, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au2"><institution>Department of Human Genetics, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au19"><institution>Department of Neurology and Neurosurgery, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Montplaisir, Jacques Y" sort="Montplaisir, Jacques Y" uniqKey="Montplaisir J" first="Jacques Y" last="Montplaisir">Jacques Y. Montplaisir</name>
<affiliation><nlm:aff id="au8"><institution>Centre d’Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au20"><institution>Department of Psychiatry, Université de Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Giladi, Nir" sort="Giladi, Nir" uniqKey="Giladi N" first="Nir" last="Giladi">Nir Giladi</name>
<affiliation><nlm:aff id="au3"><institution>Department of Neurology, Tel-Aviv Sourasky Medical Center</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au18"><institution>The Sackler Faculty of Medicine, Tel-Aviv University</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
</affiliation>
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<author><name sortKey="Rouleau, Guy A" sort="Rouleau, Guy A" uniqKey="Rouleau G" first="Guy A" last="Rouleau">Guy A. Rouleau</name>
<affiliation><nlm:aff id="au1"><institution>Montreal Neurological Institute, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au2"><institution>Department of Human Genetics, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au19"><institution>Department of Neurology and Neurosurgery, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">GBA mutations are associated with Rapid Eye Movement Sleep Behavior Disorder</title>
<author><name sortKey="Gan Or, Ziv" sort="Gan Or, Ziv" uniqKey="Gan Or Z" first="Ziv" last="Gan-Or">Ziv Gan-Or</name>
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<addr-line>Montréal, Quebec, Canada</addr-line>
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<affiliation><nlm:aff id="au2"><institution>Department of Human Genetics, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mirelman, Anat" sort="Mirelman, Anat" uniqKey="Mirelman A" first="Anat" last="Mirelman">Anat Mirelman</name>
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<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
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<author><name sortKey="Postuma, Ronald B" sort="Postuma, Ronald B" uniqKey="Postuma R" first="Ronald B" last="Postuma">Ronald B. Postuma</name>
<affiliation><nlm:aff id="au4"><institution>Department of Neurology, Montreal General Hospital</institution>
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</nlm:aff>
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<author><name sortKey="Arnulf, Isabelle" sort="Arnulf, Isabelle" uniqKey="Arnulf I" first="Isabelle" last="Arnulf">Isabelle Arnulf</name>
<affiliation><nlm:aff id="au5"><institution>Sleep Disorders Unit, Pitié Salpêtrière Hospital, Brain and Spine Institute and Sorbonne Universities, UPMC Paris 6 University</institution>
<addr-line>Paris, France</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bar Shira, Anat" sort="Bar Shira, Anat" uniqKey="Bar Shira A" first="Anat" last="Bar-Shira">Anat Bar-Shira</name>
<affiliation><nlm:aff id="au6"><institution>The Genetic Institute, Tel-Aviv Sourasky Medical Center</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dauvilliers, Yves" sort="Dauvilliers, Yves" uniqKey="Dauvilliers Y" first="Yves" last="Dauvilliers">Yves Dauvilliers</name>
<affiliation><nlm:aff id="au7"><institution>Sleep Unit, National Reference Network for Narcolepsy, Department of Neurology, Hôpital-Gui-de Chauliac, CHU Montpellier</institution>
<addr-line>Montpellier, France</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Desautels, Alex" sort="Desautels, Alex" uniqKey="Desautels A" first="Alex" last="Desautels">Alex Desautels</name>
<affiliation><nlm:aff id="au8"><institution>Centre d’Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au9"><institution>Department of Neurosciences, Université de Montréal</institution>
<addr-line>Montréal, Canada</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gagnon, Jean Francois" sort="Gagnon, Jean Francois" uniqKey="Gagnon J" first="Jean-François" last="Gagnon">Jean-François Gagnon</name>
<affiliation><nlm:aff id="au8"><institution>Centre d’Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au10"><institution>Département de psychologie, Université du Québec à Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Leblond, Claire S" sort="Leblond, Claire S" uniqKey="Leblond C" first="Claire S" last="Leblond">Claire S. Leblond</name>
<affiliation><nlm:aff id="au1"><institution>Montreal Neurological Institute, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au2"><institution>Department of Human Genetics, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Frauscher, Birgit" sort="Frauscher, Birgit" uniqKey="Frauscher B" first="Birgit" last="Frauscher">Birgit Frauscher</name>
<affiliation><nlm:aff id="au11"><institution>Sleep Disorders Clinic, Department of Neurology, Innsbruck Medical University</institution>
<addr-line>Innsbruck, Austria</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alcalay, Roy N" sort="Alcalay, Roy N" uniqKey="Alcalay R" first="Roy N" last="Alcalay">Roy N. Alcalay</name>
<affiliation><nlm:aff id="au12"><institution>Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University</institution>
<addr-line>New York, New York</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Saunders Pullman, Rachel" sort="Saunders Pullman, Rachel" uniqKey="Saunders Pullman R" first="Rachel" last="Saunders-Pullman">Rachel Saunders-Pullman</name>
<affiliation><nlm:aff id="au13"><institution>Department of Neurology, Icahn School of Medicine at Mount Sinai</institution>
<addr-line>New York, New York</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au14"><institution>Department of Neurology, Albert Einstein College of Medicine Bronx</institution>
<addr-line>New York, New York</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bressman, Susan B" sort="Bressman, Susan B" uniqKey="Bressman S" first="Susan B" last="Bressman">Susan B. Bressman</name>
<affiliation><nlm:aff id="au15"><institution>Department of Neurology, Beth Israel Medical Center</institution>
<addr-line>New York, New York</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Marder, Karen" sort="Marder, Karen" uniqKey="Marder K" first="Karen" last="Marder">Karen Marder</name>
<affiliation><nlm:aff id="au16"><institution>Columbia Presbyterian Medical Center, Columbia University</institution>
<addr-line>New York, New York</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Monaca, Christelle" sort="Monaca, Christelle" uniqKey="Monaca C" first="Christelle" last="Monaca">Christelle Monaca</name>
<affiliation><nlm:aff id="au17"><institution>Department of clinical neurophysiology and sleep center, University Lille north of France, CHU Lille</institution>
<addr-line>Lille, France</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hogl, Birgit" sort="Hogl, Birgit" uniqKey="Hogl B" first="Birgit" last="Högl">Birgit Högl</name>
<affiliation><nlm:aff id="au11"><institution>Sleep Disorders Clinic, Department of Neurology, Innsbruck Medical University</institution>
<addr-line>Innsbruck, Austria</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Orr Urtreger, Avi" sort="Orr Urtreger, Avi" uniqKey="Orr Urtreger A" first="Avi" last="Orr-Urtreger">Avi Orr-Urtreger</name>
<affiliation><nlm:aff id="au6"><institution>The Genetic Institute, Tel-Aviv Sourasky Medical Center</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au18"><institution>The Sackler Faculty of Medicine, Tel-Aviv University</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dion, Patrick A" sort="Dion, Patrick A" uniqKey="Dion P" first="Patrick A" last="Dion">Patrick A. Dion</name>
<affiliation><nlm:aff id="au1"><institution>Montreal Neurological Institute, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au2"><institution>Department of Human Genetics, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au19"><institution>Department of Neurology and Neurosurgery, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Montplaisir, Jacques Y" sort="Montplaisir, Jacques Y" uniqKey="Montplaisir J" first="Jacques Y" last="Montplaisir">Jacques Y. Montplaisir</name>
<affiliation><nlm:aff id="au8"><institution>Centre d’Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au20"><institution>Department of Psychiatry, Université de Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Giladi, Nir" sort="Giladi, Nir" uniqKey="Giladi N" first="Nir" last="Giladi">Nir Giladi</name>
<affiliation><nlm:aff id="au3"><institution>Department of Neurology, Tel-Aviv Sourasky Medical Center</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au18"><institution>The Sackler Faculty of Medicine, Tel-Aviv University</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rouleau, Guy A" sort="Rouleau, Guy A" uniqKey="Rouleau G" first="Guy A" last="Rouleau">Guy A. Rouleau</name>
<affiliation><nlm:aff id="au1"><institution>Montreal Neurological Institute, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au2"><institution>Department of Human Genetics, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="au19"><institution>Department of Neurology and Neurosurgery, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Annals of Clinical and Translational Neurology</title>
<idno type="ISSN">2328-9503</idno>
<idno type="eISSN">2328-9503</idno>
<imprint><date when="2015">2015</date>
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<front><div type="abstract" xml:lang="en"><p>Rapid eye movement sleep behavior disorder and <italic>GBA</italic>
 mutations are both associated with Parkinson's disease. The <italic>GBA</italic>
 gene was sequenced in idiopathic rapid eye movement sleep behavior disorder patients (<italic>n</italic>
 = 265), and compared to controls (<italic>n</italic>
 = 2240). Rapid eye movement sleep behavior disorder questionnaire was performed in an independent Parkinson's disease cohort (<italic>n</italic>
 = 120). <italic>GBA</italic>
 mutations carriers had an OR of 6.24 (10.2% in patients vs. 1.8% in controls, <italic>P </italic>
<<italic> </italic>
0.0001) for rapid eye movement sleep behavior disorder, and among Parkinson's disease patients, the OR for mutation carriers to have probable rapid eye movement sleep behavior disorder was 3.13 (<italic>P </italic>
=<italic> </italic>
0.039). These results demonstrate that rapid eye movement sleep behavior disorder is associated with <italic>GBA</italic>
 mutations, and that combining genetic and prodromal data may assist in identifying individuals susceptible to Parkinson's disease.</p>
</div>
</front>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">Ann Clin Transl Neurol</journal-id>
<journal-id journal-id-type="iso-abbrev">Ann Clin Transl Neurol</journal-id>
<journal-id journal-id-type="publisher-id">acn3</journal-id>
<journal-title-group><journal-title>Annals of Clinical and Translational Neurology</journal-title>
</journal-title-group>
<issn pub-type="ppub">2328-9503</issn>
<issn pub-type="epub">2328-9503</issn>
<publisher><publisher-name>John Wiley & Sons, Ltd</publisher-name>
<publisher-loc>Chichester, UK</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26401515</article-id>
<article-id pub-id-type="pmc">4574811</article-id>
<article-id pub-id-type="doi">10.1002/acn3.228</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Brief Communication</subject>
</subj-group>
</article-categories>
<title-group><article-title>GBA mutations are associated with Rapid Eye Movement Sleep Behavior Disorder</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Gan-Or</surname>
<given-names>Ziv</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mirelman</surname>
<given-names>Anat</given-names>
</name>
<xref ref-type="aff" rid="au3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Postuma</surname>
<given-names>Ronald B</given-names>
</name>
<xref ref-type="aff" rid="au4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Arnulf</surname>
<given-names>Isabelle</given-names>
</name>
<xref ref-type="aff" rid="au5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bar-Shira</surname>
<given-names>Anat</given-names>
</name>
<xref ref-type="aff" rid="au6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dauvilliers</surname>
<given-names>Yves</given-names>
</name>
<xref ref-type="aff" rid="au7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Desautels</surname>
<given-names>Alex</given-names>
</name>
<xref ref-type="aff" rid="au8">8</xref>
<xref ref-type="aff" rid="au9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gagnon</surname>
<given-names>Jean-François</given-names>
</name>
<xref ref-type="aff" rid="au8">8</xref>
<xref ref-type="aff" rid="au10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Leblond</surname>
<given-names>Claire S</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Frauscher</surname>
<given-names>Birgit</given-names>
</name>
<xref ref-type="aff" rid="au11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alcalay</surname>
<given-names>Roy N</given-names>
</name>
<xref ref-type="aff" rid="au12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Saunders-Pullman</surname>
<given-names>Rachel</given-names>
</name>
<xref ref-type="aff" rid="au13">13</xref>
<xref ref-type="aff" rid="au14">14</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bressman</surname>
<given-names>Susan B</given-names>
</name>
<xref ref-type="aff" rid="au15">15</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Marder</surname>
<given-names>Karen</given-names>
</name>
<xref ref-type="aff" rid="au16">16</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Monaca</surname>
<given-names>Christelle</given-names>
</name>
<xref ref-type="aff" rid="au17">17</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Högl</surname>
<given-names>Birgit</given-names>
</name>
<xref ref-type="aff" rid="au11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Orr-Urtreger</surname>
<given-names>Avi</given-names>
</name>
<xref ref-type="aff" rid="au6">6</xref>
<xref ref-type="aff" rid="au18">18</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dion</surname>
<given-names>Patrick A</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
<xref ref-type="aff" rid="au19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Montplaisir</surname>
<given-names>Jacques Y</given-names>
</name>
<xref ref-type="aff" rid="au8">8</xref>
<xref ref-type="aff" rid="au20">20</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Giladi</surname>
<given-names>Nir</given-names>
</name>
<xref ref-type="aff" rid="au3">3</xref>
<xref ref-type="aff" rid="au18">18</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rouleau</surname>
<given-names>Guy A</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
<xref ref-type="aff" rid="au19">19</xref>
</contrib>
<aff id="au1"><label>1</label>
<institution>Montreal Neurological Institute, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</aff>
<aff id="au2"><label>2</label>
<institution>Department of Human Genetics, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</aff>
<aff id="au3"><label>3</label>
<institution>Department of Neurology, Tel-Aviv Sourasky Medical Center</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</aff>
<aff id="au4"><label>4</label>
<institution>Department of Neurology, Montreal General Hospital</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</aff>
<aff id="au5"><label>5</label>
<institution>Sleep Disorders Unit, Pitié Salpêtrière Hospital, Brain and Spine Institute and Sorbonne Universities, UPMC Paris 6 University</institution>
<addr-line>Paris, France</addr-line>
</aff>
<aff id="au6"><label>6</label>
<institution>The Genetic Institute, Tel-Aviv Sourasky Medical Center</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</aff>
<aff id="au7"><label>7</label>
<institution>Sleep Unit, National Reference Network for Narcolepsy, Department of Neurology, Hôpital-Gui-de Chauliac, CHU Montpellier</institution>
<addr-line>Montpellier, France</addr-line>
</aff>
<aff id="au8"><label>8</label>
<institution>Centre d’Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</aff>
<aff id="au9"><label>9</label>
<institution>Department of Neurosciences, Université de Montréal</institution>
<addr-line>Montréal, Canada</addr-line>
</aff>
<aff id="au10"><label>10</label>
<institution>Département de psychologie, Université du Québec à Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</aff>
<aff id="au11"><label>11</label>
<institution>Sleep Disorders Clinic, Department of Neurology, Innsbruck Medical University</institution>
<addr-line>Innsbruck, Austria</addr-line>
</aff>
<aff id="au12"><label>12</label>
<institution>Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University</institution>
<addr-line>New York, New York</addr-line>
</aff>
<aff id="au13"><label>13</label>
<institution>Department of Neurology, Icahn School of Medicine at Mount Sinai</institution>
<addr-line>New York, New York</addr-line>
</aff>
<aff id="au14"><label>14</label>
<institution>Department of Neurology, Albert Einstein College of Medicine Bronx</institution>
<addr-line>New York, New York</addr-line>
</aff>
<aff id="au15"><label>15</label>
<institution>Department of Neurology, Beth Israel Medical Center</institution>
<addr-line>New York, New York</addr-line>
</aff>
<aff id="au16"><label>16</label>
<institution>Columbia Presbyterian Medical Center, Columbia University</institution>
<addr-line>New York, New York</addr-line>
</aff>
<aff id="au17"><label>17</label>
<institution>Department of clinical neurophysiology and sleep center, University Lille north of France, CHU Lille</institution>
<addr-line>Lille, France</addr-line>
</aff>
<aff id="au18"><label>18</label>
<institution>The Sackler Faculty of Medicine, Tel-Aviv University</institution>
<addr-line>Tel-Aviv, Israel</addr-line>
</aff>
<aff id="au19"><label>19</label>
<institution>Department of Neurology and Neurosurgery, McGill University</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</aff>
<aff id="au20"><label>20</label>
<institution>Department of Psychiatry, Université de Montréal</institution>
<addr-line>Montréal, Quebec, Canada</addr-line>
</aff>
</contrib-group>
<author-notes><corresp id="cor1"><bold>Correspondence</bold>
 Guy A. Rouleau, Montréal Neurological Institute and Hospital, 3801, University Street, Office 636, Montréal, Québec, Canada H3A 2B4. Tel: +1-514-398-2690; Fax: +1-514-398-8248; E-mail: <email>guy.rouleau@mcgill.ca</email>
, Ziv Gan-Or, Department of Human Genetics, Montréal Neurological Institute and Hospital, McGill University, 1033 Pine Avenue, West, Ludmer Pavilion, Room 327, Montreal, Quebec, Canada H3A 1A1. Tel: +1-514-398-6821; Fax: +1-514-398-8248; E-mail: <email>ziv.gan-or@mail.mcgill.ca</email>
</corresp>
<fn><p><bold>Funding Information</bold>
 This work was financially supported by the Canadian Institutes of Health Research (CIHR) and by the Michael J Fox Foundation.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>9</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>31</day>
<month>7</month>
<year>2015</year>
</pub-date>
<volume>2</volume>
<issue>9</issue>
<fpage>941</fpage>
<lpage>945</lpage>
<history><date date-type="received"><day>09</day>
<month>6</month>
<year>2015</year>
</date>
<date date-type="rev-recd"><day>29</day>
<month>6</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>30</day>
<month>6</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© 2015 The Authors. <italic>Annals of Clinical and Translational Neurology</italic>
 published by Wiley Periodicals, Inc on behalf of American Neurological Association.</copyright-statement>
<copyright-year>2015</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</license-p>
</license>
</permissions>
<abstract><p>Rapid eye movement sleep behavior disorder and <italic>GBA</italic>
 mutations are both associated with Parkinson's disease. The <italic>GBA</italic>
 gene was sequenced in idiopathic rapid eye movement sleep behavior disorder patients (<italic>n</italic>
 = 265), and compared to controls (<italic>n</italic>
 = 2240). Rapid eye movement sleep behavior disorder questionnaire was performed in an independent Parkinson's disease cohort (<italic>n</italic>
 = 120). <italic>GBA</italic>
 mutations carriers had an OR of 6.24 (10.2% in patients vs. 1.8% in controls, <italic>P </italic>
<<italic> </italic>
0.0001) for rapid eye movement sleep behavior disorder, and among Parkinson's disease patients, the OR for mutation carriers to have probable rapid eye movement sleep behavior disorder was 3.13 (<italic>P </italic>
=<italic> </italic>
0.039). These results demonstrate that rapid eye movement sleep behavior disorder is associated with <italic>GBA</italic>
 mutations, and that combining genetic and prodromal data may assist in identifying individuals susceptible to Parkinson's disease.</p>
</abstract>
</article-meta>
</front>
<body><sec><title>Introduction</title>
<p>Mutations in <italic>GBA</italic>
, the gene encoding for the enzyme Glucocerebrosidase, are common risk factors for Parkinson's disease (PD)<xref rid="b1" ref-type="bibr">1</xref>
 and Lewy Body Dementia (LBD).<xref rid="b2" ref-type="bibr">2</xref>
,<xref rid="b3" ref-type="bibr">3</xref>
 Depending on the origin of the tested population, <italic>GBA</italic>
 mutations can occur in 2–23% of PD or LBD.<xref rid="b1" ref-type="bibr">1</xref>
–<xref rid="b4" ref-type="bibr">4</xref>
<italic>GBA</italic>
 mutations have been associated with earlier age at disease onset,<xref rid="b5" ref-type="bibr">5</xref>
 and several studies demonstrated that they are also associated with cognitive decline,<xref rid="b6" ref-type="bibr">6</xref>
 dementia and autonomic dysfunction.<xref rid="b7" ref-type="bibr">7</xref>
</p>
<p>Rapid eye movement sleep behavior disorder (RBD) is a prodromal condition for both PD and LBD. Since RBD can occur many years before the onset of PD and LBD, and since more than 80% of RBD patients may convert to these synucleinopathies, it can serve as a clinical marker for PD or LBD development.<xref rid="b8" ref-type="bibr">8</xref>
 Postmortem studies demonstrated that patients with RBD, as well as patients who carried <italic>GBA</italic>
 mutations, have Lewy-Body pathology.<xref rid="b9" ref-type="bibr">9</xref>
,<xref rid="b10" ref-type="bibr">10</xref>
 Interestingly, RBD, just like <italic>GBA</italic>
 mutations, is also associated with cognitive decline/dementia<xref rid="b11" ref-type="bibr">11</xref>
 and with autonomic dysfunction<xref rid="b12" ref-type="bibr">12</xref>
 among PD patients.</p>
<p>These similarities raise the hypothesis that <italic>GBA</italic>
 mutations and RBD may be a part of the same pathway, or at least highly correlated. In this study, we aimed to examine the association between <italic>GBA</italic>
 mutations and RBD, using cohorts of idiopathic RBD and PD patients screened for RBD.</p>
</sec>
<sec sec-type="methods"><title>Methods</title>
<sec><title>Population</title>
<p>An RBD cohort of 265 unrelated idiopathic RBD patients of European ancestry was recruited through the international RBD study group. Patients were diagnosed according to the International Classification of Sleep Disorders criteria (ICSD-2) by neurologists specialized in sleep disorders. The cohort was composed of 79.6% men, with age at enrollment of 67.2 ± 9.8 years (data on gender and age was available for 255 and 264 individuals, respectively), and the <italic>GBA</italic>
 gene was fully sequenced in all. A total of 2240 controls of European origin, including 189 controls who did not have PD at the time of their recruitment from our laboratory, that were previously sequenced for <italic>GBA</italic>
 mutations,<xref rid="b13" ref-type="bibr">13</xref>
 and 2051 additional controls from similar ethnic origins that were previously published (Table S1). The controls from our lab and from the literature were not examined for RBD, therefore it is possible that some of them (the frequency of RBD is about 1% of the general population) have RBD. Such frequency among the controls would have minimal effect on the results, and it is more likely to weaken the association rather than strengthen it.</p>
<p>An independent PD cohort, including 120 Ashkenazi-Jewish patients from Tel-Aviv, Israel, previously analyzed for founder <italic>GBA</italic>
 mutations,<xref rid="b5" ref-type="bibr">5</xref>
 was screened for RBD using the RBD Screening Questionnaire (RBDSQ).<xref rid="b14" ref-type="bibr">14</xref>
 The RBDSQ was filled by a clinical researcher together with the patient, under the supervision of a neurologist, at the time of the visit in the movement disorder clinical at the Tel-Aviv Sourasky Medical Center. Neither the patients nor the interviewers were aware of the genetic status of the patients at the time of performing the RBDSQ, since the status of <italic>GBA</italic>
 mutation carriage was not disclosed prior to the interview. Therefore, since both the interviewers and the patients had no knowledge of the genetic status, it could not have affected their replies to the RBDSQ.</p>
<p>All participants signed an informed consent form, and the study protocols were approved by the respective institutional review boards or Helsinki committees.</p>
</sec>
<sec><title>Sequencing of the <italic>GBA</italic>
 gene</title>
<p>DNA was extracted from blood using a standard salting out method. The exons and exon-intron boundaries of the <italic>GBA</italic>
 gene were amplified and sequenced using specific primers designed to distinguish it from its pseudo-gene as was previously detailed.<xref rid="b13" ref-type="bibr">13</xref>
 PCRs were performed using the AmpliTaq Gold DNA Polymerase (Applied Biosystems, Foster City, CA) and the products were sequenced at the Genome Quebec Innovation Centre (Montréal, Quebec, Canada) using a 3730XL DNAnalyzer (Applied Biosystems, CA). Mutations were considered as pathogenic if they were previously associated with PD/LBD, if they are known to cause Gaucher's disease, or if they cause early stop codon.</p>
</sec>
<sec><title>Statistical analysis</title>
<p>Data are presented as mean (±SD) for continuous variables, and percentages for categorical variables. Logistic regression models, chi-square, or Fisher exact test were used for comparison of categorical variables. SPSS software v. 22 (IBM, Somers, NY) was used for all data analysis.</p>
</sec>
</sec>
<sec sec-type="results"><title>Results</title>
<p>Table<xref ref-type="table" rid="tbl1">1</xref>
 details the <italic>GBA</italic>
 mutations and variants identified in idiopathic RBD patients (<italic>n</italic>
 = 265) and our in-house controls (<italic>n</italic>
 = 189). Since the <italic>GBA</italic>
 variants c.-15A>G, p.K-27R, p.T369M and p.V460L may be considered as nonpathogenic for PD, the analysis was done with and without these variants. In both analyses, <italic>GBA</italic>
 mutations were significantly more frequent among RBD patients, with odds ratio (OR) of 2.63 (95% CI 1.30–5.29, <italic>P </italic>
=<italic> </italic>
0.0052) for all variants, and OR of 3.46 (95% CI 1.40–8.56, <italic>P </italic>
=<italic> </italic>
0.0045) for the pathogenic variants. We further compared the frequency of <italic>GBA</italic>
 mutations in the RBD cohort to a pooled control population from all studies that performed full sequencing of the <italic>GBA</italic>
 gene in European controls (Table S1). In this pooled control group, 40/2240 (1.8%) individuals were carriers of <italic>GBA</italic>
 mutations, resulting in an OR of 6.24 (95% CI 3.76–10.35, <italic>P </italic>
<<italic> </italic>
0.0001). Excluding populations from Spain, Greek and Portugal from this analysis resulted with similar risk estimates (OR = 5.72, 95% CI 3.33–9.84, <italic>P </italic>
<<italic> </italic>
0.0001).</p>
<table-wrap id="tbl1" position="float"><label>Table 1</label>
<caption><p><italic>GBA</italic>
 variants identified in RBD patients and controls</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Variation</th>
<th align="left" rowspan="1" colspan="1">RBD (<italic>n</italic>
 = 265)</th>
<th align="left" rowspan="1" colspan="1">Controls (<italic>n</italic>
 = 189)</th>
<th align="left" rowspan="1" colspan="1"><italic>P</italic>
 value</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">c.-15A>G<xref ref-type="table-fn" rid="tf1-2">1</xref>
</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.K-27R<xref ref-type="table-fn" rid="tf1-2">1</xref>
</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.R131L</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.H255Q</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.W291X</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.E326K</td>
<td align="left" rowspan="1" colspan="1">14 (5.3%)</td>
<td align="left" rowspan="1" colspan="1">3 (1.6%)</td>
<td align="left" rowspan="1" colspan="1">0.046</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.T369M<xref ref-type="table-fn" rid="tf1-2">1</xref>
</td>
<td align="left" rowspan="1" colspan="1">7 (2.6%)</td>
<td align="left" rowspan="1" colspan="1">5 (2.6%)</td>
<td align="left" rowspan="1" colspan="1">NS</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.N370S</td>
<td align="left" rowspan="1" colspan="1">5 (1.9%)</td>
<td align="left" rowspan="1" colspan="1">2 (1.1%)</td>
<td align="left" rowspan="1" colspan="1">NS</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.W378G</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.V437L</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.L444P</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">1 (0.5%)</td>
<td align="left" rowspan="1" colspan="1">NS</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">p.V460L<xref ref-type="table-fn" rid="tf1-2">1</xref>
</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" colspan="4" rowspan="1">Compound heterozygous</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> p.W179X/P.M361I</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> p.L444P/p.E326K</td>
<td align="left" rowspan="1" colspan="1">1 (0.4%)</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">NA</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Total</td>
<td align="left" rowspan="1" colspan="1">37 (14.0%)</td>
<td align="left" rowspan="1" colspan="1">11 (5.8%)</td>
<td align="left" rowspan="1" colspan="1">0.0052</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Total pathogenic</td>
<td align="left" rowspan="1" colspan="1">27 (10.2%)</td>
<td align="left" rowspan="1" colspan="1">6 (3.2%)</td>
<td align="left" rowspan="1" colspan="1">0.0045</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>RBD, rapid eye movement sleep behavior disorder; PD, Parkinson's disease; LBD, Lewy Body Dementia.</p>
</fn>
<fn id="tf1-2"><label>1</label>
<p>These variants are with unknown clinical significance, whereas the other variants are causing Gaucher's disease or associated with PD/LBD, or represent a null mutation.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>Separate analysis of the <italic>GBA</italic>
 p.E326K mutation was performed, comparing its frequency among the RBD cohort versus all studies reporting the p.E326K mutation in European control populations (including this study, Table S2, a total of 25 carriers of 2064 controls). The OR for <italic>GBA</italic>
 p.E326K mutation to have RBD was 4.55 (95% CI 2.33–8.87, <italic>P </italic>
<<italic> </italic>
0.0001).</p>
<p>Among the cohort of 120 PD patients, 19 were carriers of <italic>GBA</italic>
 mutations. Of these, 9/19 (47%) had an RBDSQ score ≥6, suggestive of RBD, compared to 24/101 (24%) among the noncarriers of <italic>GBA</italic>
 mutations (<italic>P </italic>
=<italic> </italic>
0.026). To control for the potential effects of disease duration and gender, binary regression with gender and disease duration as covariates was performed, and the OR for a <italic>GBA</italic>
 mutation carrier to have RBD was 3.13 (95% CI 1.06–9.23, <italic>P </italic>
=<italic> </italic>
0.039). Further exclusion of <italic>LRRK2</italic>
 p.G2019S mutation carriers from the analysis yielded similar results (OR = 3.10, 95% CI 1.05–9.19, <italic>P </italic>
=<italic> </italic>
0.041). The cut-off of six points was selected instead of five which is usually used, since one of the questions in the RBDSQ is “I have/had a disease of the nervous system”, therefore when screening PD patients only, this question can be regarded as redundant. When we performed the same analysis with a cut-off of five points, 11/19 (58%) of the <italic>GBA</italic>
 mutation carriers had passed the cut-off, and the OR for a <italic>GBA</italic>
 mutation carrier to have probable RBD, adjusted for gender and disease duration, was 4.06 (95% CI 1.45–11.35, <italic>P </italic>
=<italic> </italic>
0.008). The average RBDSQ questionnaire among <italic>GBA</italic>
 mutation carriers was 5.63 (±3.73), compared to 3.43 (±2.93) among the rest (<italic>P </italic>
=<italic> </italic>
0.005, Student <italic>t</italic>
-test, <italic>P </italic>
=<italic> </italic>
0.013, Mann–Whitney test). Since the PD patients and the interviewers were not aware of the <italic>GBA</italic>
 genetic status, it eliminated the possibility of biased response of <italic>GBA</italic>
 mutation carriers or noncarriers to the RBDSQ.</p>
</sec>
<sec sec-type="discussion"><title>Discussion</title>
<p>Our findings suggest a strong association between <italic>GBA</italic>
 mutations and RBD, using two independent cohorts, one with idiopathic RBD patients and the second with PD patients screened for RBD. An association between <italic>GBA</italic>
 and RBD was previously suggested in a cohort of non-PD <italic>GBA</italic>
 mutation carriers, in which a deterioration in RBD questionnaire score during follow-up was demonstrated,<xref rid="b15" ref-type="bibr">15</xref>
 but this association has never been tested in idiopathic RBD. We recently found that RBD patients share some of the genetic background of PD; single nucleotide polymorphisms in the <italic>SCARB2</italic>
 and <italic>MAPT</italic>
 regions, which were previously associated with a reduced risk for PD, were also associated with a reduced risk for RBD.<xref rid="b16" ref-type="bibr">16</xref>
 Together with this study, these data suggest that RBD is associated with several PD genetic markers, which may have major importance for future early detection of PD.</p>
<p>It is under debate whether the <italic>GBA</italic>
 p.E326K mutation is pathogenic, or a benign polymorphism. This variant does not cause Gaucher's disease,<xref rid="b17" ref-type="bibr">17</xref>
 and several studies suggested that it is not a risk factor for PD.<xref rid="b1" ref-type="bibr">1</xref>
 However, other studies demonstrated a strong association between <italic>GBA</italic>
 p.E326K mutation and PD,<xref rid="b17" ref-type="bibr">17</xref>
,<xref rid="b18" ref-type="bibr">18</xref>
 and a recent meta-analysis of genome wide association studies (GWAS) data demonstrated association with PD with an OR of 1.71 (<italic>P </italic>
=<italic> </italic>
5 × 10<sup>−8</sup>
).<xref rid="b18" ref-type="bibr">18</xref>
 Our data also support this association, as the <italic>GBA</italic>
 p.E326K variant was three to four times more frequent among RBD patients.</p>
<p>The current data also raises a possible hypothesis for the “missing heritability” in PD. The heritability of PD has been calculated as at least 27%, yet known genetic factors could only explain 3–7%.<xref rid="b19" ref-type="bibr">19</xref>
 The missing heritability, at least in part, can be hidden in subtypes of PD. That is, genetic factors may selectively contribute to a specific subtype of PD. For example, <italic>GBA</italic>
 mutations may be associated more with RBD-associated PD, whereas PD patients without RBD may have other genetic associations. This can explain the higher OR for the <italic>GBA</italic>
 p.E326K mutation in our study (4.55) compared to the PD GWAS (1.71).<xref rid="b18" ref-type="bibr">18</xref>
 Pooling such subtypes together in large GWASs may therefore allow only the identification of either strong risk factors or those that are shared between several subtypes. It is possible that subgroup analysis of these GWAS data may identify some of these genetic risk factors responsible for the missing heritability phenomenon.</p>
<p>There are a few limitations to this study. The cohort size is not considered very large, however, to the best of our knowledge it is the largest genetic cohort of idiopathic RBD published to date. The size limitation is especially true for the 19 carriers of <italic>GBA</italic>
 mutations in the PD cohort, therefore additional studies are required to confirm this association. In addition, the RBDSQ is a screening tool with potential false positive and false negative responses, yet there is no known reason for <italic>GBA</italic>
 mutation carriers with PD to have a higher false positive rate than noncarriers. Moreover, we used a strict RBDSQ score of 6 or above to suggest probable RBD, which is more appropriate in PD patients, since one of the questions is whether the individual has a neurological disorder, which is redundant when focusing on PD patients. Therefore, the different rates of probable RBD in PD patients with and without <italic>GBA</italic>
 mutations probably represent a valid support for the initial finding of overrepresentation of <italic>GBA</italic>
 mutations in RBD. However, it is worth emphasizing that the RBDSQ can only infer probable RBD and not definite RBD, therefore further studies of PD cohorts with polysomnography data are required to ascertain the association between <italic>GBA</italic>
 mutations and RBD in PD patients.</p>
<p>Perhaps the most important conclusion from our study, is its potential implications toward future neuroprotective trials. The first recommendation of the National Institute of Neurological Disorders and Stroke at the Parkinson's Disease 2014 Conference, was to “define the features and natural history of prodromal PD” and the authors further state that: “genetic risk for PD motor and nonmotor symptoms and their progression is key not only to clinical and translational research, but also to basic research, because the identified genes provide critical clues to the molecules involved.”<xref rid="b20" ref-type="bibr">20</xref>
 Beginning treatment before advanced irreversible degeneration of the substantia nigra is an important strategy for PD management. It is possible that combining screening tools for RBD with genetic data, as was done in this study, will allow the earlier identification of individuals with high susceptibility for PD, a crucial step toward achieving this goal. This hypothesis needs to be further studied in future prospective studies that will include genetic, clinical, and neuro-imaging data.</p>
</sec>
</body>
<back><ack><p>We thank the patients for their participating in this study. This work was financially supported by the Canadian Institutes of Health Research (CIHR) and by the Michael J Fox Foundation. Z. G. O. is supported by a postdoctoral fellowship from the CIHR. J. F. G. holds a Canada Research Chair on Cognitive Decline in Pathological Aging. N. G. holds the Sieratzki Chair in Neurology, Tel-Aviv University. G. A. R. holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences.</p>
</ack>
<sec><title>Conflict of Interest</title>
<p>Full disclosures were submitted to Annals of Neurology. R. B. P. reports a travel grant from Teva Neuroscience, speaker fees from Novartis Canada and consultancy fees from Roche and Biotie. I. A. reports consultancy and speaker fees from UCB Pharma. Y. D. is on the advisory board and received travel and consultancy fees from UCB Phrma, bioprojet, and Jazz Pharma. A. D. received research grants from Novartis and GlaxoSmithKline, and lecture fees from UCB Pharma and Paladin labs. S. B. reports consultancy fees from World Meds, and from Bachmann Strauss and Dystonia Medical Research Foundation for attending scientific advisory board meetings. B. H. is on the advisory board and received speaker honoraria from UCB Pharma and Mundipharma. J. Y. M. reports grants from Merck, GlaxoSmithKline, received speaking honoraria from Valeant Pharmaceutical, and Otsuka Pharmaceutical, serves on the advisory boards of Sanofi-Aventis, Servier, Merck, Jazz Pharma, Valeant Pharma, Impax Laboratories, Glaxo-SmithKline, UCB Canada, received consultancy fees from Otsuka Pharma, and Valeant Pharma. N. G. serves as consultant to Teva-Lundbeck, IntecPharma, Neuroderm, Armon Neuromedical Ltd. And Pharma Two B, and received payment for lectures at Teva-Lundbeck, Novartis and UCB.</p>
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<sec sec-type="supplementary-material"><title>Supporting Information</title>
<supplementary-material content-type="local-data" id="sd1"><label>Table S1.</label>
<caption><p>Studies of European ancestry control populations with full sequencing data of the <italic>GBA</italic>
.</p>
<p><bold>Table S2.</bold>
 Studies of European ancestry control populations with data on the <italic>GBA</italic>
 p.E326K.</p>
</caption>
<media mimetype="docx" mime-subtype="docx" xlink:href="acn30002-0941-sd1.docx" xlink:type="simple" id="d35e1669" position="anchor"></media>
</supplementary-material>
</sec>
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</pmc>
</record>

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	La maladie de Parkinson au Canada (serveur d'exploration)
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La maladie de Parkinson au Canada (serveur d'exploration)

GBA mutations are associated with Rapid Eye Movement Sleep Behavior Disorder

GBA mutations are associated with Rapid Eye Movement Sleep Behavior Disorder

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