The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
Identifieur interne : 002453 ( Istex/Corpus ); précédent : 002452; suivant : 002454The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
Auteurs : Stephan Klebe ; Jean-Louis Golmard ; Michael A. Nalls ; Mohamad Saad ; Andrew B. Singleton ; Jose M. Bras ; John Hardy ; Javier Simon-Sanchez ; Peter Heutink ; Gregor Kuhlenb Umer ; Rim Charfi ; Christine Klein ; Johann Hagenah ; Thomas Gasser ; Isabel Wurster ; Suzanne Lesage ; Delia Lorenz ; Günther Deuschl ; Franck Durif ; Pierre Pollak ; Philippe Damier ; François Tison ; Alexandra Durr ; Philippe Amouyel ; Jean-Charles Lambert ; Christophe Tzourio ; Cécilia Maubaret ; Fanny Charbonnier-Beaupel ; Khadija Tahiri ; Marie Vidailhet ; Maria Martinez ; Alexis Brice ; Jean-Christophe Corvol ; Y. Agid ; M. Anheim ; A-M Bonnet ; M. Borg ; A. Brice ; E. Broussolle ; J-C Corvol ; Ph. Damier ; A. Destée ; A. Durr ; F. Durif ; S. Klebe ; E. Lohmann ; M. Martinez ; C. Penet ; P. Pollak ; P. Krack ; O. Rascol ; F. Tison ; C. Tranchant ; M. Vérin ; F. Viallet ; Vincent Plagnol ; Jose M. Bras ; Dena G. Hernandez ; Manu Sharma ; Una-Marie Sheerin ; Mohamad Saad ; Javier Sim N-Sánchez ; Claudia Schulte ; Suzanne Lesage ; Sigurlaug Sveinbjörnsd Ttir ; Philippe Amouyel ; Sampath Arepalli ; Gavin Band ; Roger A. Barker ; Céline Bellinguez ; Yoav Ben-Shlomo ; Henk W. Berendse ; Daniela Berg ; Kailash Bhatia ; Rob Ma De Bie ; Alessandro Biffi ; Bas Bloem ; Zoltan Bochdanovits ; Michael Bonin ; Kathrin Brockmann ; Janet Brooks ; David J. Burn ; Gavin Charlesworth ; Honglei Chen ; Patrick F. Chinnery ; Sean Chong ; Carl E. Clarke ; Mark R. Cookson ; J Mark Cooper ; Jean Christophe Corvol ; Carl Counsell ; Philippe Damier ; Jean-François Dartigues ; Panos Deloukas ; David T. Dexter ; Karin D. Van Dijk ; Allissa Dillman ; Frank Durif ; Sarah Edkins ; Jonathan R. Evans ; Thomas Foltynie ; Colin Freeman ; Jianjun Gao ; Michelle Gardner ; Raphael Gibbs ; Alison Goate ; Emma Gray ; Rita Guerreiro ; Mar Gústafsson ; Clare Harris ; Garrett Hellenthal ; Jacobus J. Van Hilten ; Albert Hofman ; Albert Hollenbeck ; Janice Holton ; Michele Hu ; Xuemei Huang ; Heiko Huber ; Gavin Hudson ; Sarah E. Hunt ; Johanna Huttenlocher ; Thomas Illig ; Pálmi V. J Nsson ; Cordelia Langford ; Andrew Lees ; Peter Lichtner ; Patricia Limousin ; Grisel Lopez ; Delia Lorenz ; Alisdair Mcneill ; Catriona Moorby ; Huw Morris ; Karen E. Morrison ; Ese Mudanohwo ; Sean S. O'Sullivan ; Justin Pearson ; Richard Pearson ; Joel S. Perlmutter ; Hjörvar Pétursson ; Matti Pirinen ; Pierre Pollak ; Bart Post ; Simon Potter ; Bernard Ravina ; Tamas Revesz ; Olaf Riess ; Fernando Rivadeneira ; Patrizia Rizzu ; Mina Ryten ; Stephen Sawcer ; Anthony Schapira ; Hans Scheffer ; Karen Shaw ; Ira Shoulson ; Ellen Sidransky ; Rohan De Silva ; Colin Smith ; Chris Ca Spencer ; Hreinn Stefánsson ; Stacy Steinberg ; Joanna D. Stockton ; Amy Strange ; Zhan Su ; Kevin Talbot ; Carlie M. Tanner ; Avazeh Tashakkori-Ghanbaria ; François Tison ; Daniah Trabzuni ; Bryan J. Traynor ; G. Uitterlinden ; Jana Vandrovcova ; Daan Velseboer ; Marie Vidailhet ; Damjan Vukcevic ; Robert Walker ; Bart Van De Warrenburg ; Michael E. Weale ; Mirdhu Wickremaratchi ; Nigel Williams ; Caroline H. Williams-Gray ; Sophie Winder-Rhodes ; Maria Martinez ; Peter Donnelly ; John Hardy ; Peter Heutink ; Alexis Brice ; Thomas Gasser ; Nicholas W. Wood ; Andrew B. SingletonSource :
- Journal of Neurology, Neurosurgery & Psychiatry [ 0022-3050 ] ; 2013-06.
Abstract
The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
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DOI: 10.1136/jnnp-2012-304475
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Nalls</name><affiliation><mods:affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Saad, Mohamad" sort="Saad, Mohamad" uniqKey="Saad M" first="Mohamad" last="Saad">Mohamad Saad</name><affiliation><mods:affiliation>INSERM U1043, CPTP, Toulouse, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Paul Sabatier University, Toulouse, France</mods:affiliation></affiliation></author><author><name sortKey="Singleton, Andrew B" sort="Singleton, Andrew B" uniqKey="Singleton A" first="Andrew B" last="Singleton">Andrew B. Singleton</name><affiliation><mods:affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Bras, Jose M" sort="Bras, Jose M" uniqKey="Bras J" first="Jose M" last="Bras">Jose M. Bras</name><affiliation><mods:affiliation>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><mods:affiliation>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Simon Sanchez, Javier" sort="Simon Sanchez, Javier" uniqKey="Simon Sanchez J" first="Javier" last="Simon-Sanchez">Javier Simon-Sanchez</name><affiliation><mods:affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Heutink, Peter" sort="Heutink, Peter" uniqKey="Heutink P" first="Peter" last="Heutink">Peter Heutink</name><affiliation><mods:affiliation>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Kuhlenb Umer, Gregor" sort="Kuhlenb Umer, Gregor" uniqKey="Kuhlenb Umer G" first="Gregor" last="Kuhlenb Umer">Gregor Kuhlenb Umer</name><affiliation><mods:affiliation>Institute of Experimental Medicine, Christian-Albrechts University, Kiel, Germany</mods:affiliation></affiliation></author><author><name sortKey="Charfi, Rim" sort="Charfi, Rim" uniqKey="Charfi R" first="Rim" last="Charfi">Rim Charfi</name><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Faculté de Médecine de Tunis, Université de Tunis El Manar, Centre National de Pharmacovigilance de Tunis, Service de Pharmacologie Clinique, Tunis, Tunisia</mods:affiliation></affiliation></author><author><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name><affiliation><mods:affiliation>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Hagenah, Johann" sort="Hagenah, Johann" uniqKey="Hagenah J" first="Johann" last="Hagenah">Johann Hagenah</name><affiliation><mods:affiliation>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Wurster, Isabel" sort="Wurster, Isabel" uniqKey="Wurster I" first="Isabel" last="Wurster">Isabel Wurster</name><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Lesage, Suzanne" sort="Lesage, Suzanne" uniqKey="Lesage S" first="Suzanne" last="Lesage">Suzanne Lesage</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Lorenz, Delia" sort="Lorenz, Delia" uniqKey="Lorenz D" first="Delia" last="Lorenz">Delia Lorenz</name><affiliation><mods:affiliation>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</mods:affiliation></affiliation></author><author><name sortKey="Deuschl, Gunther" sort="Deuschl, Gunther" uniqKey="Deuschl G" first="Günther" last="Deuschl">Günther Deuschl</name><affiliation><mods:affiliation>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</mods:affiliation></affiliation></author><author><name sortKey="Durif, Franck" sort="Durif, Franck" uniqKey="Durif F" first="Franck" last="Durif">Franck Durif</name><affiliation><mods:affiliation>Hôpital Gabriel Montpied, CHU de Grenoble, Department of Neurology, Clermont-Ferrand, France</mods:affiliation></affiliation></author><author><name sortKey="Pollak, Pierre" sort="Pollak, Pierre" uniqKey="Pollak P" first="Pierre" last="Pollak">Pierre Pollak</name><affiliation><mods:affiliation>CHU de Grenoble, Department of Neurology, Grenoble, France</mods:affiliation></affiliation></author><author><name sortKey="Damier, Philippe" sort="Damier, Philippe" uniqKey="Damier P" first="Philippe" last="Damier">Philippe Damier</name><affiliation><mods:affiliation>CHU de Nantes, Centre d'Investigation Clinique, Nantes, France</mods:affiliation></affiliation></author><author><name sortKey="Tison, Francois" sort="Tison, Francois" uniqKey="Tison F" first="François" last="Tison">François Tison</name><affiliation><mods:affiliation>Hôpital Haut-Lévêque, Department of Neurology, Pessac, France</mods:affiliation></affiliation></author><author><name sortKey="Durr, Alexandra" sort="Durr, Alexandra" uniqKey="Durr A" first="Alexandra" last="Durr">Alexandra Durr</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name><affiliation><mods:affiliation>INSERM, U744, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Institut Pasteur de Lille, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Université Lille-Nord de France, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name><affiliation><mods:affiliation>INSERM, U744, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Institut Pasteur de Lille, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Université Lille-Nord de France, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Tzourio, Christophe" sort="Tzourio, Christophe" uniqKey="Tzourio C" first="Christophe" last="Tzourio">Christophe Tzourio</name><affiliation><mods:affiliation>Université Pierre et Marie Curie—Paris 6, CNRS 7225 CRICM, ER4-UPMC Modélisation en recherche clinique, Hôpital Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>INSERM UMR_S708, Neuroépidémiologie, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Maubaret, Cecilia" sort="Maubaret, Cecilia" uniqKey="Maubaret C" first="Cécilia" last="Maubaret">Cécilia Maubaret</name><affiliation><mods:affiliation>INSERM U897, Université Bordeaux Ségalen, Bordeaux, France</mods:affiliation></affiliation></author><author><name sortKey="Charbonnier Beaupel, Fanny" sort="Charbonnier Beaupel, Fanny" uniqKey="Charbonnier Beaupel F" first="Fanny" last="Charbonnier-Beaupel">Fanny Charbonnier-Beaupel</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Tahiri, Khadija" sort="Tahiri, Khadija" uniqKey="Tahiri K" first="Khadija" last="Tahiri">Khadija Tahiri</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Vidailhet, Marie" sort="Vidailhet, Marie" uniqKey="Vidailhet M" first="Marie" last="Vidailhet">Marie Vidailhet</name><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>“Movement Disorders and Basal Ganglia: Pathophysiology and experimental Therapeutics”, INSERM, UMR_S975, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Martinez, Maria" sort="Martinez, Maria" uniqKey="Martinez M" first="Maria" last="Martinez">Maria Martinez</name><affiliation><mods:affiliation>INSERM U1043, CPTP, Toulouse, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Paul Sabatier University, Toulouse, France</mods:affiliation></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Corvol, Jean Christophe" sort="Corvol, Jean Christophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author wicri:is="80%"><name sortKey="Agid, Y" sort="Agid, Y" uniqKey="Agid Y" first="Y" last="Agid">Y. Agid</name></author><author wicri:is="80%"><name sortKey="Anheim, M" sort="Anheim, M" uniqKey="Anheim M" first="M" last="Anheim">M. Anheim</name></author><author wicri:is="80%"><name sortKey="Bonnet, A M" sort="Bonnet, A M" uniqKey="Bonnet A" first="A-M" last="Bonnet">A-M Bonnet</name></author><author wicri:is="80%"><name sortKey="Borg, M" sort="Borg, M" uniqKey="Borg M" first="M" last="Borg">M. Borg</name></author><author wicri:is="80%"><name sortKey="Brice, A" sort="Brice, A" uniqKey="Brice A" first="A." last="Brice">A. Brice</name></author><author wicri:is="80%"><name sortKey="Broussolle, E" sort="Broussolle, E" uniqKey="Broussolle E" first="E" last="Broussolle">E. Broussolle</name></author><author wicri:is="80%"><name sortKey="Corvol, J C" sort="Corvol, J C" uniqKey="Corvol J" first="J-C" last="Corvol">J-C Corvol</name></author><author wicri:is="80%"><name sortKey="Damier, Ph" sort="Damier, Ph" uniqKey="Damier P" first="Ph." last="Damier">Ph. Damier</name></author><author wicri:is="80%"><name sortKey="Destee, A" sort="Destee, A" uniqKey="Destee A" first="A." last="Destée">A. Destée</name></author><author wicri:is="80%"><name sortKey="Durr, A" sort="Durr, A" uniqKey="Durr A" first="A" last="Durr">A. Durr</name></author><author wicri:is="80%"><name sortKey="Durif, F" sort="Durif, F" uniqKey="Durif F" first="F" last="Durif">F. Durif</name></author><author wicri:is="80%"><name sortKey="Klebe, S" sort="Klebe, S" uniqKey="Klebe S" first="S" last="Klebe">S. Klebe</name></author><author wicri:is="80%"><name sortKey="Lohmann, E" sort="Lohmann, E" uniqKey="Lohmann E" first="E" last="Lohmann">E. Lohmann</name></author><author wicri:is="80%"><name sortKey="Martinez, M" sort="Martinez, M" uniqKey="Martinez M" first="M" last="Martinez">M. Martinez</name></author><author wicri:is="80%"><name sortKey="Penet, C" sort="Penet, C" uniqKey="Penet C" first="C" last="Penet">C. Penet</name></author><author wicri:is="80%"><name sortKey="Pollak, P" sort="Pollak, P" uniqKey="Pollak P" first="P" last="Pollak">P. Pollak</name></author><author wicri:is="80%"><name sortKey="Krack, P" sort="Krack, P" uniqKey="Krack P" first="P" last="Krack">P. Krack</name></author><author wicri:is="80%"><name sortKey="Rascol, O" sort="Rascol, O" uniqKey="Rascol O" first="O" last="Rascol">O. Rascol</name></author><author wicri:is="80%"><name sortKey="Tison, F" sort="Tison, F" uniqKey="Tison F" first="F" last="Tison">F. Tison</name></author><author wicri:is="80%"><name sortKey="Tranchant, C" sort="Tranchant, C" uniqKey="Tranchant C" first="C" last="Tranchant">C. Tranchant</name></author><author wicri:is="80%"><name sortKey="Verin, M" sort="Verin, M" uniqKey="Verin M" first="M" last="Vérin">M. Vérin</name></author><author wicri:is="80%"><name sortKey="Viallet, F" sort="Viallet, F" uniqKey="Viallet F" first="F" last="Viallet">F. Viallet</name></author><author wicri:is="80%"><name sortKey="Plagnol, Vincent" sort="Plagnol, Vincent" uniqKey="Plagnol V" first="Vincent" last="Plagnol">Vincent Plagnol</name></author><author wicri:is="80%"><name sortKey="Bras, Jose M" sort="Bras, Jose M" uniqKey="Bras J" first="Jose M" last="Bras">Jose M. Bras</name></author><author wicri:is="80%"><name sortKey="Hernandez, Dena G" sort="Hernandez, Dena G" uniqKey="Hernandez D" first="Dena G" last="Hernandez">Dena G. 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Barker</name></author><author wicri:is="80%"><name sortKey="Bellinguez, Celine" sort="Bellinguez, Celine" uniqKey="Bellinguez C" first="Céline" last="Bellinguez">Céline Bellinguez</name></author><author wicri:is="80%"><name sortKey="Ben Shlomo, Yoav" sort="Ben Shlomo, Yoav" uniqKey="Ben Shlomo Y" first="Yoav" last="Ben-Shlomo">Yoav Ben-Shlomo</name></author><author wicri:is="80%"><name sortKey="Berendse, Henk W" sort="Berendse, Henk W" uniqKey="Berendse H" first="Henk W" last="Berendse">Henk W. Berendse</name></author><author wicri:is="80%"><name sortKey="Berg, Daniela" sort="Berg, Daniela" uniqKey="Berg D" first="Daniela" last="Berg">Daniela Berg</name></author><author wicri:is="80%"><name sortKey="Bhatia, Kailash" sort="Bhatia, Kailash" uniqKey="Bhatia K" first="Kailash" last="Bhatia">Kailash Bhatia</name></author><author wicri:is="80%"><name sortKey="De Bie, Rob Ma" sort="De Bie, Rob Ma" uniqKey="De Bie R" first="Rob Ma" last="De Bie">Rob Ma De Bie</name></author><author wicri:is="80%"><name sortKey="Biffi, Alessandro" sort="Biffi, Alessandro" uniqKey="Biffi A" first="Alessandro" last="Biffi">Alessandro Biffi</name></author><author wicri:is="80%"><name sortKey="Bloem, Bas" sort="Bloem, Bas" uniqKey="Bloem B" first="Bas" last="Bloem">Bas Bloem</name></author><author wicri:is="80%"><name sortKey="Bochdanovits, Zoltan" sort="Bochdanovits, Zoltan" uniqKey="Bochdanovits Z" first="Zoltan" last="Bochdanovits">Zoltan Bochdanovits</name></author><author wicri:is="80%"><name sortKey="Bonin, Michael" sort="Bonin, Michael" uniqKey="Bonin M" first="Michael" last="Bonin">Michael Bonin</name></author><author wicri:is="80%"><name sortKey="Brockmann, Kathrin" sort="Brockmann, Kathrin" uniqKey="Brockmann K" first="Kathrin" last="Brockmann">Kathrin Brockmann</name></author><author wicri:is="80%"><name sortKey="Brooks, Janet" sort="Brooks, Janet" uniqKey="Brooks J" first="Janet" last="Brooks">Janet Brooks</name></author><author wicri:is="80%"><name sortKey="Burn, David J" sort="Burn, David J" uniqKey="Burn D" first="David J" last="Burn">David J. Burn</name></author><author wicri:is="80%"><name sortKey="Charlesworth, Gavin" sort="Charlesworth, Gavin" uniqKey="Charlesworth G" first="Gavin" last="Charlesworth">Gavin Charlesworth</name></author><author wicri:is="80%"><name sortKey="Chen, Honglei" sort="Chen, Honglei" uniqKey="Chen H" first="Honglei" last="Chen">Honglei Chen</name></author><author wicri:is="80%"><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F" last="Chinnery">Patrick F. Chinnery</name></author><author wicri:is="80%"><name sortKey="Chong, Sean" sort="Chong, Sean" uniqKey="Chong S" first="Sean" last="Chong">Sean Chong</name></author><author wicri:is="80%"><name sortKey="Clarke, Carl E" sort="Clarke, Carl E" uniqKey="Clarke C" first="Carl E" last="Clarke">Carl E. Clarke</name></author><author wicri:is="80%"><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R" last="Cookson">Mark R. Cookson</name></author><author wicri:is="80%"><name sortKey="Cooper, J Mark" sort="Cooper, J Mark" uniqKey="Cooper J" first="J Mark" last="Cooper">J Mark Cooper</name></author><author wicri:is="80%"><name sortKey="Corvol, Jean Christophe" sort="Corvol, Jean Christophe" uniqKey="Corvol J" first="Jean Christophe" last="Corvol">Jean Christophe Corvol</name></author><author wicri:is="80%"><name sortKey="Counsell, Carl" sort="Counsell, Carl" uniqKey="Counsell C" first="Carl" last="Counsell">Carl Counsell</name></author><author wicri:is="80%"><name sortKey="Damier, Philippe" sort="Damier, Philippe" uniqKey="Damier P" first="Philippe" last="Damier">Philippe Damier</name></author><author wicri:is="80%"><name sortKey="Dartigues, Jean Francois" sort="Dartigues, Jean Francois" uniqKey="Dartigues J" first="Jean-François" last="Dartigues">Jean-François Dartigues</name></author><author wicri:is="80%"><name sortKey="Deloukas, Panos" sort="Deloukas, Panos" uniqKey="Deloukas P" first="Panos" last="Deloukas">Panos Deloukas</name></author><author wicri:is="80%"><name sortKey="Dexter, David T" sort="Dexter, David T" uniqKey="Dexter D" first="David T" last="Dexter">David T. Dexter</name></author><author wicri:is="80%"><name sortKey="Van Dijk, Karin D" sort="Van Dijk, Karin D" uniqKey="Van Dijk K" first="Karin D" last="Van Dijk">Karin D. Van Dijk</name></author><author wicri:is="80%"><name sortKey="Dillman, Allissa" sort="Dillman, Allissa" uniqKey="Dillman A" first="Allissa" last="Dillman">Allissa Dillman</name></author><author wicri:is="80%"><name sortKey="Durif, Frank" sort="Durif, Frank" uniqKey="Durif F" first="Frank" last="Durif">Frank Durif</name></author><author wicri:is="80%"><name sortKey="Edkins, Sarah" sort="Edkins, Sarah" uniqKey="Edkins S" first="Sarah" last="Edkins">Sarah Edkins</name></author><author wicri:is="80%"><name sortKey="Evans, Jonathan R" sort="Evans, Jonathan R" uniqKey="Evans J" first="Jonathan R" last="Evans">Jonathan R. Evans</name></author><author wicri:is="80%"><name sortKey="Foltynie, Thomas" sort="Foltynie, Thomas" uniqKey="Foltynie T" first="Thomas" last="Foltynie">Thomas Foltynie</name></author><author wicri:is="80%"><name sortKey="Freeman, Colin" sort="Freeman, Colin" uniqKey="Freeman C" first="Colin" last="Freeman">Colin Freeman</name></author><author wicri:is="80%"><name sortKey="Gao, Jianjun" sort="Gao, Jianjun" uniqKey="Gao J" first="Jianjun" last="Gao">Jianjun Gao</name></author><author wicri:is="80%"><name sortKey="Gardner, Michelle" sort="Gardner, Michelle" uniqKey="Gardner M" first="Michelle" last="Gardner">Michelle Gardner</name></author><author wicri:is="80%"><name sortKey="Gibbs, Raphael" sort="Gibbs, Raphael" uniqKey="Gibbs R" first="Raphael" last="Gibbs">Raphael Gibbs</name></author><author wicri:is="80%"><name sortKey="Goate, Alison" sort="Goate, Alison" uniqKey="Goate A" first="Alison" last="Goate">Alison Goate</name></author><author wicri:is="80%"><name sortKey="Gray, Emma" sort="Gray, Emma" uniqKey="Gray E" first="Emma" last="Gray">Emma Gray</name></author><author wicri:is="80%"><name sortKey="Guerreiro, Rita" sort="Guerreiro, Rita" uniqKey="Guerreiro R" first="Rita" last="Guerreiro">Rita Guerreiro</name></author><author wicri:is="80%"><name sortKey="Gustafsson, Mar" sort="Gustafsson, Mar" uniqKey="Gustafsson " first=" Mar" last="Gústafsson"> Mar Gústafsson</name></author><author wicri:is="80%"><name sortKey="Harris, Clare" sort="Harris, Clare" uniqKey="Harris C" first="Clare" last="Harris">Clare Harris</name></author><author wicri:is="80%"><name sortKey="Hellenthal, Garrett" sort="Hellenthal, Garrett" uniqKey="Hellenthal G" first="Garrett" last="Hellenthal">Garrett Hellenthal</name></author><author wicri:is="80%"><name sortKey="Van Hilten, Jacobus J" sort="Van Hilten, Jacobus J" uniqKey="Van Hilten J" first="Jacobus J" last="Van Hilten">Jacobus J. Van Hilten</name></author><author wicri:is="80%"><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name></author><author wicri:is="80%"><name sortKey="Hollenbeck, Albert" sort="Hollenbeck, Albert" uniqKey="Hollenbeck A" first="Albert" last="Hollenbeck">Albert Hollenbeck</name></author><author wicri:is="80%"><name sortKey="Holton, Janice" sort="Holton, Janice" uniqKey="Holton J" first="Janice" last="Holton">Janice Holton</name></author><author wicri:is="80%"><name sortKey="Hu, Michele" sort="Hu, Michele" uniqKey="Hu M" first="Michele" last="Hu">Michele Hu</name></author><author wicri:is="80%"><name sortKey="Huang, Xuemei" sort="Huang, Xuemei" uniqKey="Huang X" first="Xuemei" last="Huang">Xuemei Huang</name></author><author wicri:is="80%"><name sortKey="Huber, Heiko" sort="Huber, Heiko" uniqKey="Huber H" first="Heiko" last="Huber">Heiko Huber</name></author><author wicri:is="80%"><name sortKey="Hudson, Gavin" sort="Hudson, Gavin" uniqKey="Hudson G" first="Gavin" last="Hudson">Gavin Hudson</name></author><author wicri:is="80%"><name sortKey="Hunt, Sarah E" sort="Hunt, Sarah E" uniqKey="Hunt S" first="Sarah E" last="Hunt">Sarah E. Hunt</name></author><author wicri:is="80%"><name sortKey="Huttenlocher, Johanna" sort="Huttenlocher, Johanna" uniqKey="Huttenlocher J" first="Johanna" last="Huttenlocher">Johanna Huttenlocher</name></author><author wicri:is="80%"><name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name></author><author wicri:is="80%"><name sortKey="J Nsson, Palmi V" sort="J Nsson, Palmi V" uniqKey="J Nsson P" first="Pálmi V" last="J Nsson">Pálmi V. J Nsson</name></author><author wicri:is="80%"><name sortKey="Langford, Cordelia" sort="Langford, Cordelia" uniqKey="Langford C" first="Cordelia" last="Langford">Cordelia Langford</name></author><author wicri:is="80%"><name sortKey="Lees, Andrew" sort="Lees, Andrew" uniqKey="Lees A" first="Andrew" last="Lees">Andrew Lees</name></author><author wicri:is="80%"><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name></author><author wicri:is="80%"><name sortKey="Limousin, Patricia" sort="Limousin, Patricia" uniqKey="Limousin P" first="Patricia" last="Limousin">Patricia Limousin</name></author><author wicri:is="80%"><name sortKey="Lopez, Grisel" sort="Lopez, Grisel" uniqKey="Lopez G" first="Grisel" last="Lopez">Grisel Lopez</name></author><author wicri:is="80%"><name sortKey="Lorenz, Delia" sort="Lorenz, Delia" uniqKey="Lorenz D" first="Delia" last="Lorenz">Delia Lorenz</name></author><author wicri:is="80%"><name sortKey="Mcneill, Alisdair" sort="Mcneill, Alisdair" uniqKey="Mcneill A" first="Alisdair" last="Mcneill">Alisdair Mcneill</name></author><author wicri:is="80%"><name sortKey="Moorby, Catriona" sort="Moorby, Catriona" uniqKey="Moorby C" first="Catriona" last="Moorby">Catriona Moorby</name></author><author wicri:is="80%"><name sortKey="Morris, Huw" sort="Morris, Huw" uniqKey="Morris H" first="Huw" last="Morris">Huw Morris</name></author><author wicri:is="80%"><name sortKey="Morrison, Karen E" sort="Morrison, Karen E" uniqKey="Morrison K" first="Karen E" last="Morrison">Karen E. Morrison</name></author><author wicri:is="80%"><name sortKey="Mudanohwo, Ese" sort="Mudanohwo, Ese" uniqKey="Mudanohwo E" first="Ese" last="Mudanohwo">Ese Mudanohwo</name></author><author wicri:is="80%"><name sortKey="O Sullivan, Sean S" sort="O Sullivan, Sean S" uniqKey="O Sullivan S" first="Sean S" last="O'Sullivan">Sean S. O'Sullivan</name></author><author wicri:is="80%"><name sortKey="Pearson, Justin" sort="Pearson, Justin" uniqKey="Pearson J" first="Justin" last="Pearson">Justin Pearson</name></author><author wicri:is="80%"><name sortKey="Pearson, Richard" sort="Pearson, Richard" uniqKey="Pearson R" first="Richard" last="Pearson">Richard Pearson</name></author><author wicri:is="80%"><name sortKey="Perlmutter, Joel S" sort="Perlmutter, Joel S" uniqKey="Perlmutter J" first="Joel S" last="Perlmutter">Joel S. 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Stockton</name></author><author wicri:is="80%"><name sortKey="Strange, Amy" sort="Strange, Amy" uniqKey="Strange A" first="Amy" last="Strange">Amy Strange</name></author><author wicri:is="80%"><name sortKey="Su, Zhan" sort="Su, Zhan" uniqKey="Su Z" first="Zhan" last="Su">Zhan Su</name></author><author wicri:is="80%"><name sortKey="Talbot, Kevin" sort="Talbot, Kevin" uniqKey="Talbot K" first="Kevin" last="Talbot">Kevin Talbot</name></author><author wicri:is="80%"><name sortKey="Tanner, Carlie M" sort="Tanner, Carlie M" uniqKey="Tanner C" first="Carlie M" last="Tanner">Carlie M. Tanner</name></author><author wicri:is="80%"><name sortKey="Tashakkori Ghanbaria, Avazeh" sort="Tashakkori Ghanbaria, Avazeh" uniqKey="Tashakkori Ghanbaria A" first="Avazeh" last="Tashakkori-Ghanbaria">Avazeh Tashakkori-Ghanbaria</name></author><author wicri:is="80%"><name sortKey="Tison, Francois" sort="Tison, Francois" uniqKey="Tison F" first="François" last="Tison">François Tison</name></author><author wicri:is="80%"><name sortKey="Trabzuni, Daniah" sort="Trabzuni, Daniah" uniqKey="Trabzuni D" first="Daniah" last="Trabzuni">Daniah Trabzuni</name></author><author wicri:is="80%"><name sortKey="Traynor, Bryan J" sort="Traynor, Bryan J" uniqKey="Traynor B" first="Bryan J" last="Traynor">Bryan J. Traynor</name></author><author wicri:is="80%"><name sortKey="Uitterlinden, G" sort="Uitterlinden, G" uniqKey="Uitterlinden G" first="G" last="Uitterlinden">G. Uitterlinden</name></author><author wicri:is="80%"><name sortKey="Vandrovcova, Jana" sort="Vandrovcova, Jana" uniqKey="Vandrovcova J" first="Jana" last="Vandrovcova">Jana Vandrovcova</name></author><author wicri:is="80%"><name sortKey="Velseboer, Daan" sort="Velseboer, Daan" uniqKey="Velseboer D" first="Daan" last="Velseboer">Daan Velseboer</name></author><author wicri:is="80%"><name sortKey="Vidailhet, Marie" sort="Vidailhet, Marie" uniqKey="Vidailhet M" first="Marie" last="Vidailhet">Marie Vidailhet</name></author><author wicri:is="80%"><name sortKey="Vukcevic, Damjan" sort="Vukcevic, Damjan" uniqKey="Vukcevic D" first="Damjan" last="Vukcevic">Damjan Vukcevic</name></author><author wicri:is="80%"><name sortKey="Walker, Robert" sort="Walker, Robert" uniqKey="Walker R" first="Robert" last="Walker">Robert Walker</name></author><author wicri:is="80%"><name sortKey="Van De Warrenburg, Bart" sort="Van De Warrenburg, Bart" uniqKey="Van De Warrenburg B" first="Bart" last="Van De Warrenburg">Bart Van De Warrenburg</name></author><author wicri:is="80%"><name sortKey="Weale, Michael E" sort="Weale, Michael E" uniqKey="Weale M" first="Michael E" last="Weale">Michael E. Weale</name></author><author wicri:is="80%"><name sortKey="Wickremaratchi, Mirdhu" sort="Wickremaratchi, Mirdhu" uniqKey="Wickremaratchi M" first="Mirdhu" last="Wickremaratchi">Mirdhu Wickremaratchi</name></author><author wicri:is="80%"><name sortKey="Williams, Nigel" sort="Williams, Nigel" uniqKey="Williams N" first="Nigel" last="Williams">Nigel Williams</name></author><author wicri:is="80%"><name sortKey="Williams Gray, Caroline H" sort="Williams Gray, Caroline H" uniqKey="Williams Gray C" first="Caroline H" last="Williams-Gray">Caroline H. Williams-Gray</name></author><author wicri:is="80%"><name sortKey="Winder Rhodes, Sophie" sort="Winder Rhodes, Sophie" uniqKey="Winder Rhodes S" first="Sophie" last="Winder-Rhodes">Sophie Winder-Rhodes</name></author><author wicri:is="80%"><name sortKey="Martinez, Maria" sort="Martinez, Maria" uniqKey="Martinez M" first="Maria" last="Martinez">Maria Martinez</name></author><author wicri:is="80%"><name sortKey="Donnelly, Peter" sort="Donnelly, Peter" uniqKey="Donnelly P" first="Peter" last="Donnelly">Peter Donnelly</name></author><author wicri:is="80%"><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name></author><author wicri:is="80%"><name sortKey="Heutink, Peter" sort="Heutink, Peter" uniqKey="Heutink P" first="Peter" last="Heutink">Peter Heutink</name></author><author wicri:is="80%"><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name></author><author wicri:is="80%"><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name></author><author wicri:is="80%"><name sortKey="Wood, Nicholas W" sort="Wood, Nicholas W" uniqKey="Wood N" first="Nicholas W" last="Wood">Nicholas W. Wood</name></author><author wicri:is="80%"><name sortKey="Singleton, Andrew B" sort="Singleton, Andrew B" uniqKey="Singleton A" first="Andrew B" last="Singleton">Andrew B. Singleton</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:01332202B2E3FECDAEE2F34EA137D7ED1671829B</idno><date when="2013" year="2013">2013</date><idno type="doi">10.1136/jnnp-2012-304475</idno><idno type="url">https://api.istex.fr/document/01332202B2E3FECDAEE2F34EA137D7ED1671829B/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">002453</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">002453</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism</title><author><name sortKey="Klebe, Stephan" sort="Klebe, Stephan" uniqKey="Klebe S" first="Stephan" last="Klebe">Stephan Klebe</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, University Hospital Würzburg, Würzburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Golmard, Jean Louis" sort="Golmard, Jean Louis" uniqKey="Golmard J" first="Jean-Louis" last="Golmard">Jean-Louis Golmard</name><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Biostatistics, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Nalls, Michael A" sort="Nalls, Michael A" uniqKey="Nalls M" first="Michael A" last="Nalls">Michael A. Nalls</name><affiliation><mods:affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Saad, Mohamad" sort="Saad, Mohamad" uniqKey="Saad M" first="Mohamad" last="Saad">Mohamad Saad</name><affiliation><mods:affiliation>INSERM U1043, CPTP, Toulouse, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Paul Sabatier University, Toulouse, France</mods:affiliation></affiliation></author><author><name sortKey="Singleton, Andrew B" sort="Singleton, Andrew B" uniqKey="Singleton A" first="Andrew B" last="Singleton">Andrew B. Singleton</name><affiliation><mods:affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Bras, Jose M" sort="Bras, Jose M" uniqKey="Bras J" first="Jose M" last="Bras">Jose M. Bras</name><affiliation><mods:affiliation>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><mods:affiliation>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Simon Sanchez, Javier" sort="Simon Sanchez, Javier" uniqKey="Simon Sanchez J" first="Javier" last="Simon-Sanchez">Javier Simon-Sanchez</name><affiliation><mods:affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Heutink, Peter" sort="Heutink, Peter" uniqKey="Heutink P" first="Peter" last="Heutink">Peter Heutink</name><affiliation><mods:affiliation>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Kuhlenb Umer, Gregor" sort="Kuhlenb Umer, Gregor" uniqKey="Kuhlenb Umer G" first="Gregor" last="Kuhlenb Umer">Gregor Kuhlenb Umer</name><affiliation><mods:affiliation>Institute of Experimental Medicine, Christian-Albrechts University, Kiel, Germany</mods:affiliation></affiliation></author><author><name sortKey="Charfi, Rim" sort="Charfi, Rim" uniqKey="Charfi R" first="Rim" last="Charfi">Rim Charfi</name><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Faculté de Médecine de Tunis, Université de Tunis El Manar, Centre National de Pharmacovigilance de Tunis, Service de Pharmacologie Clinique, Tunis, Tunisia</mods:affiliation></affiliation></author><author><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name><affiliation><mods:affiliation>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Hagenah, Johann" sort="Hagenah, Johann" uniqKey="Hagenah J" first="Johann" last="Hagenah">Johann Hagenah</name><affiliation><mods:affiliation>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Wurster, Isabel" sort="Wurster, Isabel" uniqKey="Wurster I" first="Isabel" last="Wurster">Isabel Wurster</name><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Lesage, Suzanne" sort="Lesage, Suzanne" uniqKey="Lesage S" first="Suzanne" last="Lesage">Suzanne Lesage</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Lorenz, Delia" sort="Lorenz, Delia" uniqKey="Lorenz D" first="Delia" last="Lorenz">Delia Lorenz</name><affiliation><mods:affiliation>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</mods:affiliation></affiliation></author><author><name sortKey="Deuschl, Gunther" sort="Deuschl, Gunther" uniqKey="Deuschl G" first="Günther" last="Deuschl">Günther Deuschl</name><affiliation><mods:affiliation>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</mods:affiliation></affiliation></author><author><name sortKey="Durif, Franck" sort="Durif, Franck" uniqKey="Durif F" first="Franck" last="Durif">Franck Durif</name><affiliation><mods:affiliation>Hôpital Gabriel Montpied, CHU de Grenoble, Department of Neurology, Clermont-Ferrand, France</mods:affiliation></affiliation></author><author><name sortKey="Pollak, Pierre" sort="Pollak, Pierre" uniqKey="Pollak P" first="Pierre" last="Pollak">Pierre Pollak</name><affiliation><mods:affiliation>CHU de Grenoble, Department of Neurology, Grenoble, France</mods:affiliation></affiliation></author><author><name sortKey="Damier, Philippe" sort="Damier, Philippe" uniqKey="Damier P" first="Philippe" last="Damier">Philippe Damier</name><affiliation><mods:affiliation>CHU de Nantes, Centre d'Investigation Clinique, Nantes, France</mods:affiliation></affiliation></author><author><name sortKey="Tison, Francois" sort="Tison, Francois" uniqKey="Tison F" first="François" last="Tison">François Tison</name><affiliation><mods:affiliation>Hôpital Haut-Lévêque, Department of Neurology, Pessac, France</mods:affiliation></affiliation></author><author><name sortKey="Durr, Alexandra" sort="Durr, Alexandra" uniqKey="Durr A" first="Alexandra" last="Durr">Alexandra Durr</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name><affiliation><mods:affiliation>INSERM, U744, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Institut Pasteur de Lille, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Université Lille-Nord de France, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name><affiliation><mods:affiliation>INSERM, U744, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Institut Pasteur de Lille, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Université Lille-Nord de France, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Tzourio, Christophe" sort="Tzourio, Christophe" uniqKey="Tzourio C" first="Christophe" last="Tzourio">Christophe Tzourio</name><affiliation><mods:affiliation>Université Pierre et Marie Curie—Paris 6, CNRS 7225 CRICM, ER4-UPMC Modélisation en recherche clinique, Hôpital Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>INSERM UMR_S708, Neuroépidémiologie, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Maubaret, Cecilia" sort="Maubaret, Cecilia" uniqKey="Maubaret C" first="Cécilia" last="Maubaret">Cécilia Maubaret</name><affiliation><mods:affiliation>INSERM U897, Université Bordeaux Ségalen, Bordeaux, France</mods:affiliation></affiliation></author><author><name sortKey="Charbonnier Beaupel, Fanny" sort="Charbonnier Beaupel, Fanny" uniqKey="Charbonnier Beaupel F" first="Fanny" last="Charbonnier-Beaupel">Fanny Charbonnier-Beaupel</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Tahiri, Khadija" sort="Tahiri, Khadija" uniqKey="Tahiri K" first="Khadija" last="Tahiri">Khadija Tahiri</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Vidailhet, Marie" sort="Vidailhet, Marie" uniqKey="Vidailhet M" first="Marie" last="Vidailhet">Marie Vidailhet</name><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>“Movement Disorders and Basal Ganglia: Pathophysiology and experimental Therapeutics”, INSERM, UMR_S975, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Martinez, Maria" sort="Martinez, Maria" uniqKey="Martinez M" first="Maria" last="Martinez">Maria Martinez</name><affiliation><mods:affiliation>INSERM U1043, CPTP, Toulouse, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Paul Sabatier University, Toulouse, France</mods:affiliation></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Corvol, Jean Christophe" sort="Corvol, Jean Christophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name><affiliation><mods:affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author wicri:is="80%"><name sortKey="Agid, Y" sort="Agid, Y" uniqKey="Agid Y" first="Y" last="Agid">Y. Agid</name></author><author wicri:is="80%"><name sortKey="Anheim, M" sort="Anheim, M" uniqKey="Anheim M" first="M" last="Anheim">M. Anheim</name></author><author wicri:is="80%"><name sortKey="Bonnet, A M" sort="Bonnet, A M" uniqKey="Bonnet A" first="A-M" last="Bonnet">A-M Bonnet</name></author><author wicri:is="80%"><name sortKey="Borg, M" sort="Borg, M" uniqKey="Borg M" first="M" last="Borg">M. Borg</name></author><author wicri:is="80%"><name sortKey="Brice, A" sort="Brice, A" uniqKey="Brice A" first="A." last="Brice">A. Brice</name></author><author wicri:is="80%"><name sortKey="Broussolle, E" sort="Broussolle, E" uniqKey="Broussolle E" first="E" last="Broussolle">E. Broussolle</name></author><author wicri:is="80%"><name sortKey="Corvol, J C" sort="Corvol, J C" uniqKey="Corvol J" first="J-C" last="Corvol">J-C Corvol</name></author><author wicri:is="80%"><name sortKey="Damier, Ph" sort="Damier, Ph" uniqKey="Damier P" first="Ph." last="Damier">Ph. Damier</name></author><author wicri:is="80%"><name sortKey="Destee, A" sort="Destee, A" uniqKey="Destee A" first="A." last="Destée">A. Destée</name></author><author wicri:is="80%"><name sortKey="Durr, A" sort="Durr, A" uniqKey="Durr A" first="A" last="Durr">A. Durr</name></author><author wicri:is="80%"><name sortKey="Durif, F" sort="Durif, F" uniqKey="Durif F" first="F" last="Durif">F. Durif</name></author><author wicri:is="80%"><name sortKey="Klebe, S" sort="Klebe, S" uniqKey="Klebe S" first="S" last="Klebe">S. Klebe</name></author><author wicri:is="80%"><name sortKey="Lohmann, E" sort="Lohmann, E" uniqKey="Lohmann E" first="E" last="Lohmann">E. Lohmann</name></author><author wicri:is="80%"><name sortKey="Martinez, M" sort="Martinez, M" uniqKey="Martinez M" first="M" last="Martinez">M. Martinez</name></author><author wicri:is="80%"><name sortKey="Penet, C" sort="Penet, C" uniqKey="Penet C" first="C" last="Penet">C. Penet</name></author><author wicri:is="80%"><name sortKey="Pollak, P" sort="Pollak, P" uniqKey="Pollak P" first="P" last="Pollak">P. Pollak</name></author><author wicri:is="80%"><name sortKey="Krack, P" sort="Krack, P" uniqKey="Krack P" first="P" last="Krack">P. Krack</name></author><author wicri:is="80%"><name sortKey="Rascol, O" sort="Rascol, O" uniqKey="Rascol O" first="O" last="Rascol">O. Rascol</name></author><author wicri:is="80%"><name sortKey="Tison, F" sort="Tison, F" uniqKey="Tison F" first="F" last="Tison">F. Tison</name></author><author wicri:is="80%"><name sortKey="Tranchant, C" sort="Tranchant, C" uniqKey="Tranchant C" first="C" last="Tranchant">C. Tranchant</name></author><author wicri:is="80%"><name sortKey="Verin, M" sort="Verin, M" uniqKey="Verin M" first="M" last="Vérin">M. Vérin</name></author><author wicri:is="80%"><name sortKey="Viallet, F" sort="Viallet, F" uniqKey="Viallet F" first="F" last="Viallet">F. Viallet</name></author><author wicri:is="80%"><name sortKey="Plagnol, Vincent" sort="Plagnol, Vincent" uniqKey="Plagnol V" first="Vincent" last="Plagnol">Vincent Plagnol</name></author><author wicri:is="80%"><name sortKey="Bras, Jose M" sort="Bras, Jose M" uniqKey="Bras J" first="Jose M" last="Bras">Jose M. Bras</name></author><author wicri:is="80%"><name sortKey="Hernandez, Dena G" sort="Hernandez, Dena G" uniqKey="Hernandez D" first="Dena G" last="Hernandez">Dena G. 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Barker</name></author><author wicri:is="80%"><name sortKey="Bellinguez, Celine" sort="Bellinguez, Celine" uniqKey="Bellinguez C" first="Céline" last="Bellinguez">Céline Bellinguez</name></author><author wicri:is="80%"><name sortKey="Ben Shlomo, Yoav" sort="Ben Shlomo, Yoav" uniqKey="Ben Shlomo Y" first="Yoav" last="Ben-Shlomo">Yoav Ben-Shlomo</name></author><author wicri:is="80%"><name sortKey="Berendse, Henk W" sort="Berendse, Henk W" uniqKey="Berendse H" first="Henk W" last="Berendse">Henk W. Berendse</name></author><author wicri:is="80%"><name sortKey="Berg, Daniela" sort="Berg, Daniela" uniqKey="Berg D" first="Daniela" last="Berg">Daniela Berg</name></author><author wicri:is="80%"><name sortKey="Bhatia, Kailash" sort="Bhatia, Kailash" uniqKey="Bhatia K" first="Kailash" last="Bhatia">Kailash Bhatia</name></author><author wicri:is="80%"><name sortKey="De Bie, Rob Ma" sort="De Bie, Rob Ma" uniqKey="De Bie R" first="Rob Ma" last="De Bie">Rob Ma De Bie</name></author><author wicri:is="80%"><name sortKey="Biffi, Alessandro" sort="Biffi, Alessandro" uniqKey="Biffi A" first="Alessandro" last="Biffi">Alessandro Biffi</name></author><author wicri:is="80%"><name sortKey="Bloem, Bas" sort="Bloem, Bas" uniqKey="Bloem B" first="Bas" last="Bloem">Bas Bloem</name></author><author wicri:is="80%"><name sortKey="Bochdanovits, Zoltan" sort="Bochdanovits, Zoltan" uniqKey="Bochdanovits Z" first="Zoltan" last="Bochdanovits">Zoltan Bochdanovits</name></author><author wicri:is="80%"><name sortKey="Bonin, Michael" sort="Bonin, Michael" uniqKey="Bonin M" first="Michael" last="Bonin">Michael Bonin</name></author><author wicri:is="80%"><name sortKey="Brockmann, Kathrin" sort="Brockmann, Kathrin" uniqKey="Brockmann K" first="Kathrin" last="Brockmann">Kathrin Brockmann</name></author><author wicri:is="80%"><name sortKey="Brooks, Janet" sort="Brooks, Janet" uniqKey="Brooks J" first="Janet" last="Brooks">Janet Brooks</name></author><author wicri:is="80%"><name sortKey="Burn, David J" sort="Burn, David J" uniqKey="Burn D" first="David J" last="Burn">David J. Burn</name></author><author wicri:is="80%"><name sortKey="Charlesworth, Gavin" sort="Charlesworth, Gavin" uniqKey="Charlesworth G" first="Gavin" last="Charlesworth">Gavin Charlesworth</name></author><author wicri:is="80%"><name sortKey="Chen, Honglei" sort="Chen, Honglei" uniqKey="Chen H" first="Honglei" last="Chen">Honglei Chen</name></author><author wicri:is="80%"><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F" last="Chinnery">Patrick F. Chinnery</name></author><author wicri:is="80%"><name sortKey="Chong, Sean" sort="Chong, Sean" uniqKey="Chong S" first="Sean" last="Chong">Sean Chong</name></author><author wicri:is="80%"><name sortKey="Clarke, Carl E" sort="Clarke, Carl E" uniqKey="Clarke C" first="Carl E" last="Clarke">Carl E. Clarke</name></author><author wicri:is="80%"><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R" last="Cookson">Mark R. Cookson</name></author><author wicri:is="80%"><name sortKey="Cooper, J Mark" sort="Cooper, J Mark" uniqKey="Cooper J" first="J Mark" last="Cooper">J Mark Cooper</name></author><author wicri:is="80%"><name sortKey="Corvol, Jean Christophe" sort="Corvol, Jean Christophe" uniqKey="Corvol J" first="Jean Christophe" last="Corvol">Jean Christophe Corvol</name></author><author wicri:is="80%"><name sortKey="Counsell, Carl" sort="Counsell, Carl" uniqKey="Counsell C" first="Carl" last="Counsell">Carl Counsell</name></author><author wicri:is="80%"><name sortKey="Damier, Philippe" sort="Damier, Philippe" uniqKey="Damier P" first="Philippe" last="Damier">Philippe Damier</name></author><author wicri:is="80%"><name sortKey="Dartigues, Jean Francois" sort="Dartigues, Jean Francois" uniqKey="Dartigues J" first="Jean-François" last="Dartigues">Jean-François Dartigues</name></author><author wicri:is="80%"><name sortKey="Deloukas, Panos" sort="Deloukas, Panos" uniqKey="Deloukas P" first="Panos" last="Deloukas">Panos Deloukas</name></author><author wicri:is="80%"><name sortKey="Dexter, David T" sort="Dexter, David T" uniqKey="Dexter D" first="David T" last="Dexter">David T. Dexter</name></author><author wicri:is="80%"><name sortKey="Van Dijk, Karin D" sort="Van Dijk, Karin D" uniqKey="Van Dijk K" first="Karin D" last="Van Dijk">Karin D. Van Dijk</name></author><author wicri:is="80%"><name sortKey="Dillman, Allissa" sort="Dillman, Allissa" uniqKey="Dillman A" first="Allissa" last="Dillman">Allissa Dillman</name></author><author wicri:is="80%"><name sortKey="Durif, Frank" sort="Durif, Frank" uniqKey="Durif F" first="Frank" last="Durif">Frank Durif</name></author><author wicri:is="80%"><name sortKey="Edkins, Sarah" sort="Edkins, Sarah" uniqKey="Edkins S" first="Sarah" last="Edkins">Sarah Edkins</name></author><author wicri:is="80%"><name sortKey="Evans, Jonathan R" sort="Evans, Jonathan R" uniqKey="Evans J" first="Jonathan R" last="Evans">Jonathan R. Evans</name></author><author wicri:is="80%"><name sortKey="Foltynie, Thomas" sort="Foltynie, Thomas" uniqKey="Foltynie T" first="Thomas" last="Foltynie">Thomas Foltynie</name></author><author wicri:is="80%"><name sortKey="Freeman, Colin" sort="Freeman, Colin" uniqKey="Freeman C" first="Colin" last="Freeman">Colin Freeman</name></author><author wicri:is="80%"><name sortKey="Gao, Jianjun" sort="Gao, Jianjun" uniqKey="Gao J" first="Jianjun" last="Gao">Jianjun Gao</name></author><author wicri:is="80%"><name sortKey="Gardner, Michelle" sort="Gardner, Michelle" uniqKey="Gardner M" first="Michelle" last="Gardner">Michelle Gardner</name></author><author wicri:is="80%"><name sortKey="Gibbs, Raphael" sort="Gibbs, Raphael" uniqKey="Gibbs R" first="Raphael" last="Gibbs">Raphael Gibbs</name></author><author wicri:is="80%"><name sortKey="Goate, Alison" sort="Goate, Alison" uniqKey="Goate A" first="Alison" last="Goate">Alison Goate</name></author><author wicri:is="80%"><name sortKey="Gray, Emma" sort="Gray, Emma" uniqKey="Gray E" first="Emma" last="Gray">Emma Gray</name></author><author wicri:is="80%"><name sortKey="Guerreiro, Rita" sort="Guerreiro, Rita" uniqKey="Guerreiro R" first="Rita" last="Guerreiro">Rita Guerreiro</name></author><author wicri:is="80%"><name sortKey="Gustafsson, Mar" sort="Gustafsson, Mar" uniqKey="Gustafsson " first=" Mar" last="Gústafsson"> Mar Gústafsson</name></author><author wicri:is="80%"><name sortKey="Harris, Clare" sort="Harris, Clare" uniqKey="Harris C" first="Clare" last="Harris">Clare Harris</name></author><author wicri:is="80%"><name sortKey="Hellenthal, Garrett" sort="Hellenthal, Garrett" uniqKey="Hellenthal G" first="Garrett" last="Hellenthal">Garrett Hellenthal</name></author><author wicri:is="80%"><name sortKey="Van Hilten, Jacobus J" sort="Van Hilten, Jacobus J" uniqKey="Van Hilten J" first="Jacobus J" last="Van Hilten">Jacobus J. Van Hilten</name></author><author wicri:is="80%"><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name></author><author wicri:is="80%"><name sortKey="Hollenbeck, Albert" sort="Hollenbeck, Albert" uniqKey="Hollenbeck A" first="Albert" last="Hollenbeck">Albert Hollenbeck</name></author><author wicri:is="80%"><name sortKey="Holton, Janice" sort="Holton, Janice" uniqKey="Holton J" first="Janice" last="Holton">Janice Holton</name></author><author wicri:is="80%"><name sortKey="Hu, Michele" sort="Hu, Michele" uniqKey="Hu M" first="Michele" last="Hu">Michele Hu</name></author><author wicri:is="80%"><name sortKey="Huang, Xuemei" sort="Huang, Xuemei" uniqKey="Huang X" first="Xuemei" last="Huang">Xuemei Huang</name></author><author wicri:is="80%"><name sortKey="Huber, Heiko" sort="Huber, Heiko" uniqKey="Huber H" first="Heiko" last="Huber">Heiko Huber</name></author><author wicri:is="80%"><name sortKey="Hudson, Gavin" sort="Hudson, Gavin" uniqKey="Hudson G" first="Gavin" last="Hudson">Gavin Hudson</name></author><author wicri:is="80%"><name sortKey="Hunt, Sarah E" sort="Hunt, Sarah E" uniqKey="Hunt S" first="Sarah E" last="Hunt">Sarah E. Hunt</name></author><author wicri:is="80%"><name sortKey="Huttenlocher, Johanna" sort="Huttenlocher, Johanna" uniqKey="Huttenlocher J" first="Johanna" last="Huttenlocher">Johanna Huttenlocher</name></author><author wicri:is="80%"><name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name></author><author wicri:is="80%"><name sortKey="J Nsson, Palmi V" sort="J Nsson, Palmi V" uniqKey="J Nsson P" first="Pálmi V" last="J Nsson">Pálmi V. J Nsson</name></author><author wicri:is="80%"><name sortKey="Langford, Cordelia" sort="Langford, Cordelia" uniqKey="Langford C" first="Cordelia" last="Langford">Cordelia Langford</name></author><author wicri:is="80%"><name sortKey="Lees, Andrew" sort="Lees, Andrew" uniqKey="Lees A" first="Andrew" last="Lees">Andrew Lees</name></author><author wicri:is="80%"><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name></author><author wicri:is="80%"><name sortKey="Limousin, Patricia" sort="Limousin, Patricia" uniqKey="Limousin P" first="Patricia" last="Limousin">Patricia Limousin</name></author><author wicri:is="80%"><name sortKey="Lopez, Grisel" sort="Lopez, Grisel" uniqKey="Lopez G" first="Grisel" last="Lopez">Grisel Lopez</name></author><author wicri:is="80%"><name sortKey="Lorenz, Delia" sort="Lorenz, Delia" uniqKey="Lorenz D" first="Delia" last="Lorenz">Delia Lorenz</name></author><author wicri:is="80%"><name sortKey="Mcneill, Alisdair" sort="Mcneill, Alisdair" uniqKey="Mcneill A" first="Alisdair" last="Mcneill">Alisdair Mcneill</name></author><author wicri:is="80%"><name sortKey="Moorby, Catriona" sort="Moorby, Catriona" uniqKey="Moorby C" first="Catriona" last="Moorby">Catriona Moorby</name></author><author wicri:is="80%"><name sortKey="Morris, Huw" sort="Morris, Huw" uniqKey="Morris H" first="Huw" last="Morris">Huw Morris</name></author><author wicri:is="80%"><name sortKey="Morrison, Karen E" sort="Morrison, Karen E" uniqKey="Morrison K" first="Karen E" last="Morrison">Karen E. Morrison</name></author><author wicri:is="80%"><name sortKey="Mudanohwo, Ese" sort="Mudanohwo, Ese" uniqKey="Mudanohwo E" first="Ese" last="Mudanohwo">Ese Mudanohwo</name></author><author wicri:is="80%"><name sortKey="O Sullivan, Sean S" sort="O Sullivan, Sean S" uniqKey="O Sullivan S" first="Sean S" last="O'Sullivan">Sean S. O'Sullivan</name></author><author wicri:is="80%"><name sortKey="Pearson, Justin" sort="Pearson, Justin" uniqKey="Pearson J" first="Justin" last="Pearson">Justin Pearson</name></author><author wicri:is="80%"><name sortKey="Pearson, Richard" sort="Pearson, Richard" uniqKey="Pearson R" first="Richard" last="Pearson">Richard Pearson</name></author><author wicri:is="80%"><name sortKey="Perlmutter, Joel S" sort="Perlmutter, Joel S" uniqKey="Perlmutter J" first="Joel S" last="Perlmutter">Joel S. 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Stockton</name></author><author wicri:is="80%"><name sortKey="Strange, Amy" sort="Strange, Amy" uniqKey="Strange A" first="Amy" last="Strange">Amy Strange</name></author><author wicri:is="80%"><name sortKey="Su, Zhan" sort="Su, Zhan" uniqKey="Su Z" first="Zhan" last="Su">Zhan Su</name></author><author wicri:is="80%"><name sortKey="Talbot, Kevin" sort="Talbot, Kevin" uniqKey="Talbot K" first="Kevin" last="Talbot">Kevin Talbot</name></author><author wicri:is="80%"><name sortKey="Tanner, Carlie M" sort="Tanner, Carlie M" uniqKey="Tanner C" first="Carlie M" last="Tanner">Carlie M. Tanner</name></author><author wicri:is="80%"><name sortKey="Tashakkori Ghanbaria, Avazeh" sort="Tashakkori Ghanbaria, Avazeh" uniqKey="Tashakkori Ghanbaria A" first="Avazeh" last="Tashakkori-Ghanbaria">Avazeh Tashakkori-Ghanbaria</name></author><author wicri:is="80%"><name sortKey="Tison, Francois" sort="Tison, Francois" uniqKey="Tison F" first="François" last="Tison">François Tison</name></author><author wicri:is="80%"><name sortKey="Trabzuni, Daniah" sort="Trabzuni, Daniah" uniqKey="Trabzuni D" first="Daniah" last="Trabzuni">Daniah Trabzuni</name></author><author wicri:is="80%"><name sortKey="Traynor, Bryan J" sort="Traynor, Bryan J" uniqKey="Traynor B" first="Bryan J" last="Traynor">Bryan J. Traynor</name></author><author wicri:is="80%"><name sortKey="Uitterlinden, G" sort="Uitterlinden, G" uniqKey="Uitterlinden G" first="G" last="Uitterlinden">G. Uitterlinden</name></author><author wicri:is="80%"><name sortKey="Vandrovcova, Jana" sort="Vandrovcova, Jana" uniqKey="Vandrovcova J" first="Jana" last="Vandrovcova">Jana Vandrovcova</name></author><author wicri:is="80%"><name sortKey="Velseboer, Daan" sort="Velseboer, Daan" uniqKey="Velseboer D" first="Daan" last="Velseboer">Daan Velseboer</name></author><author wicri:is="80%"><name sortKey="Vidailhet, Marie" sort="Vidailhet, Marie" uniqKey="Vidailhet M" first="Marie" last="Vidailhet">Marie Vidailhet</name></author><author wicri:is="80%"><name sortKey="Vukcevic, Damjan" sort="Vukcevic, Damjan" uniqKey="Vukcevic D" first="Damjan" last="Vukcevic">Damjan Vukcevic</name></author><author wicri:is="80%"><name sortKey="Walker, Robert" sort="Walker, Robert" uniqKey="Walker R" first="Robert" last="Walker">Robert Walker</name></author><author wicri:is="80%"><name sortKey="Van De Warrenburg, Bart" sort="Van De Warrenburg, Bart" uniqKey="Van De Warrenburg B" first="Bart" last="Van De Warrenburg">Bart Van De Warrenburg</name></author><author wicri:is="80%"><name sortKey="Weale, Michael E" sort="Weale, Michael E" uniqKey="Weale M" first="Michael E" last="Weale">Michael E. Weale</name></author><author wicri:is="80%"><name sortKey="Wickremaratchi, Mirdhu" sort="Wickremaratchi, Mirdhu" uniqKey="Wickremaratchi M" first="Mirdhu" last="Wickremaratchi">Mirdhu Wickremaratchi</name></author><author wicri:is="80%"><name sortKey="Williams, Nigel" sort="Williams, Nigel" uniqKey="Williams N" first="Nigel" last="Williams">Nigel Williams</name></author><author wicri:is="80%"><name sortKey="Williams Gray, Caroline H" sort="Williams Gray, Caroline H" uniqKey="Williams Gray C" first="Caroline H" last="Williams-Gray">Caroline H. Williams-Gray</name></author><author wicri:is="80%"><name sortKey="Winder Rhodes, Sophie" sort="Winder Rhodes, Sophie" uniqKey="Winder Rhodes S" first="Sophie" last="Winder-Rhodes">Sophie Winder-Rhodes</name></author><author wicri:is="80%"><name sortKey="Martinez, Maria" sort="Martinez, Maria" uniqKey="Martinez M" first="Maria" last="Martinez">Maria Martinez</name></author><author wicri:is="80%"><name sortKey="Donnelly, Peter" sort="Donnelly, Peter" uniqKey="Donnelly P" first="Peter" last="Donnelly">Peter Donnelly</name></author><author wicri:is="80%"><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name></author><author wicri:is="80%"><name sortKey="Heutink, Peter" sort="Heutink, Peter" uniqKey="Heutink P" first="Peter" last="Heutink">Peter Heutink</name></author><author wicri:is="80%"><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name></author><author wicri:is="80%"><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name></author><author wicri:is="80%"><name sortKey="Wood, Nicholas W" sort="Wood, Nicholas W" uniqKey="Wood N" first="Nicholas W" last="Wood">Nicholas W. Wood</name></author><author wicri:is="80%"><name sortKey="Singleton, Andrew B" sort="Singleton, Andrew B" uniqKey="Singleton A" first="Andrew B" last="Singleton">Andrew B. Singleton</name></author></analytic><monogr></monogr><series><title level="j">Journal of Neurology, Neurosurgery & Psychiatry</title><title level="j" type="abbrev">J Neurol Neurosurg Psychiatry</title><idno type="ISSN">0022-3050</idno><idno type="eISSN">1468-330X</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2013-06">2013-06</date><biblScope unit="volume">84</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="666">666</biblScope></imprint><idno type="ISSN">0022-3050</idno></series><idno type="istex">01332202B2E3FECDAEE2F34EA137D7ED1671829B</idno><idno type="DOI">10.1136/jnnp-2012-304475</idno><idno type="href">jnnp-84-666.pdf</idno><idno type="ArticleID">jnnp-2012-304475</idno><idno type="PMID">23408064</idno><idno type="local">jnnp;84/6/666</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-3050</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.</div></front></TEI><istex><corpusName>bmj</corpusName><author><json:item><name>Stephan Klebe</name><affiliations><json:string>INSERM, UMR_S975, CR-ICM, Paris, France</json:string><json:string>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string><json:string>INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string><json:string>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string><json:string>Department of Neurology, University Hospital Würzburg, Würzburg, Germany</json:string></affiliations></json:item><json:item><name>Jean-Louis Golmard</name><affiliations><json:string>Assistance Publique Hôpitaux de Paris, Department of Biostatistics, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string></affiliations></json:item><json:item><name>Michael A Nalls</name><affiliations><json:string>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</json:string></affiliations></json:item><json:item><name>Mohamad Saad</name><affiliations><json:string>INSERM U1043, CPTP, Toulouse, France</json:string><json:string>Paul Sabatier University, Toulouse, France</json:string></affiliations></json:item><json:item><name>Andrew B Singleton</name><affiliations><json:string>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</json:string></affiliations></json:item><json:item><name>Jose M Bras</name><affiliations><json:string>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</json:string></affiliations></json:item><json:item><name>John Hardy</name><affiliations><json:string>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</json:string></affiliations></json:item><json:item><name>Javier Simon-Sanchez</name><affiliations><json:string>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</json:string><json:string>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</json:string></affiliations></json:item><json:item><name>Peter Heutink</name><affiliations><json:string>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</json:string></affiliations></json:item><json:item><name>Gregor Kuhlenbäumer</name><affiliations><json:string>Institute of Experimental Medicine, Christian-Albrechts University, Kiel, Germany</json:string></affiliations></json:item><json:item><name>Rim Charfi</name><affiliations><json:string>Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string><json:string>Faculté de Médecine de Tunis, Université de Tunis El Manar, Centre National de Pharmacovigilance de Tunis, Service de Pharmacologie Clinique, Tunis, Tunisia</json:string></affiliations></json:item><json:item><name>Christine Klein</name><affiliations><json:string>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item><json:item><name>Johann Hagenah</name><affiliations><json:string>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item><json:item><name>Thomas Gasser</name><affiliations><json:string>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string><json:string>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Isabel Wurster</name><affiliations><json:string>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string><json:string>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Suzanne Lesage</name><affiliations><json:string>INSERM, UMR_S975, CR-ICM, Paris, France</json:string><json:string>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string></affiliations></json:item><json:item><name>Delia Lorenz</name><affiliations><json:string>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</json:string></affiliations></json:item><json:item><name>Günther Deuschl</name><affiliations><json:string>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</json:string></affiliations></json:item><json:item><name>Franck Durif</name><affiliations><json:string>Hôpital Gabriel Montpied, CHU de Grenoble, Department of Neurology, Clermont-Ferrand, France</json:string></affiliations></json:item><json:item><name>Pierre Pollak</name><affiliations><json:string>CHU de Grenoble, Department of Neurology, Grenoble, France</json:string></affiliations></json:item><json:item><name>Philippe Damier</name><affiliations><json:string>CHU de Nantes, Centre d'Investigation Clinique, Nantes, France</json:string></affiliations></json:item><json:item><name>François Tison</name><affiliations><json:string>Hôpital Haut-Lévêque, Department of Neurology, Pessac, France</json:string></affiliations></json:item><json:item><name>Alexandra Durr</name><affiliations><json:string>INSERM, UMR_S975, CR-ICM, Paris, France</json:string><json:string>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string></affiliations></json:item><json:item><name>Philippe Amouyel</name><affiliations><json:string>INSERM, U744, Lille, France</json:string><json:string>Institut Pasteur de Lille, Lille, France</json:string><json:string>Université Lille-Nord de France, Lille, France</json:string></affiliations></json:item><json:item><name>Jean-Charles Lambert</name><affiliations><json:string>INSERM, U744, Lille, France</json:string><json:string>Institut Pasteur de Lille, Lille, France</json:string><json:string>Université Lille-Nord de France, Lille, France</json:string></affiliations></json:item><json:item><name>Christophe Tzourio</name><affiliations><json:string>Université Pierre et Marie Curie—Paris 6, CNRS 7225 CRICM, ER4-UPMC Modélisation en recherche clinique, Hôpital Pitié-Salpêtrière, Paris, France</json:string><json:string>INSERM UMR_S708, Neuroépidémiologie, Paris, France</json:string></affiliations></json:item><json:item><name>Cécilia Maubaret</name><affiliations><json:string>INSERM U897, Université Bordeaux Ségalen, Bordeaux, France</json:string></affiliations></json:item><json:item><name>Fanny Charbonnier-Beaupel</name><affiliations><json:string>INSERM, UMR_S975, CR-ICM, Paris, France</json:string><json:string>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string></affiliations></json:item><json:item><name>Khadija Tahiri</name><affiliations><json:string>INSERM, UMR_S975, CR-ICM, Paris, France</json:string><json:string>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string></affiliations></json:item><json:item><name>Marie Vidailhet</name><affiliations><json:string>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string><json:string>“Movement Disorders and Basal Ganglia: Pathophysiology and experimental Therapeutics”, INSERM, UMR_S975, Paris, France</json:string></affiliations></json:item><json:item><name>Maria Martinez</name><affiliations><json:string>INSERM U1043, CPTP, Toulouse, France</json:string><json:string>Paul Sabatier University, Toulouse, France</json:string></affiliations></json:item><json:item><name>Alexis Brice</name><affiliations><json:string>INSERM, UMR_S975, CR-ICM, Paris, France</json:string><json:string>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string><json:string>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string></affiliations></json:item><json:item><name>Jean-Christophe Corvol</name><affiliations><json:string>INSERM, UMR_S975, CR-ICM, Paris, France</json:string><json:string>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</json:string><json:string>INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string><json:string>Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Open access</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Movement Disorders</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Neurogenetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's Disease</value></json:item></subject><articleId><json:string>jnnp-2012-304475</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.</abstract><qualityIndicators><score>10</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595.276 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>4</keywordCount><abstractCharCount>1646</abstractCharCount><pdfWordCount>8095</pdfWordCount><pdfCharCount>57239</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>256</abstractWordCount></qualityIndicators><title>The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism</title><pmid><json:string>23408064</json:string></pmid><corporate><json:item><name>French Parkinson's Disease Genetics Study Group and the International Parkinson's Disease Genomics Consortium 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Williams</name></json:item><json:item><name>Caroline H Williams-Gray</name></json:item><json:item><name>Sophie Winder-Rhodes</name></json:item><json:item><name>Maria Martinez</name></json:item><json:item><name>Peter Donnelly</name></json:item><json:item><name>John Hardy</name></json:item><json:item><name>Peter Heutink</name></json:item><json:item><name>Alexis Brice</name></json:item><json:item><name>Thomas Gasser</name></json:item><json:item><name>Nicholas W Wood</name></json:item><json:item><name>Andrew B Singleton</name></json:item></author_non-byline><categories><wos><json:string>social science</json:string><json:string>psychiatry</json:string><json:string>science</json:string><json:string>surgery</json:string><json:string>clinical neurology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>neurology & neurosurgery</json:string></scienceMetrix></categories><publicationDate>2013</publicationDate><copyrightDate>2013</copyrightDate><doi><json:string>10.1136/jnnp-2012-304475</json:string></doi><id>01332202B2E3FECDAEE2F34EA137D7ED1671829B</id><score>0.24572057</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/01332202B2E3FECDAEE2F34EA137D7ED1671829B/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/01332202B2E3FECDAEE2F34EA137D7ED1671829B/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/01332202B2E3FECDAEE2F34EA137D7ED1671829B/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>BMJ Publishing Group Ltd</publisher><availability status="free"><p>Open Access</p></availability><date>2013-02-13</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism</title><author><orgName>French Parkinson's Disease Genetics Study Group and the International Parkinson's Disease Genomics Consortium (IPDGC)</orgName></author><author xml:id="author-2"><persName><forename type="first">Stephan</forename><surname>Klebe</surname></persName><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>Department of Neurology, University Hospital Würzburg, Würzburg, Germany</affiliation></author><author xml:id="author-3"><persName><forename type="first">Jean-Louis</forename><surname>Golmard</surname></persName><affiliation>Assistance Publique Hôpitaux de Paris, Department of Biostatistics, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">Michael A</forename><surname>Nalls</surname></persName><affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</affiliation></author><author xml:id="author-5"><persName><forename type="first">Mohamad</forename><surname>Saad</surname></persName><affiliation>INSERM U1043, CPTP, Toulouse, France</affiliation><affiliation>Paul Sabatier University, Toulouse, France</affiliation></author><author xml:id="author-6"><persName><forename type="first">Andrew B</forename><surname>Singleton</surname></persName><affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</affiliation></author><author xml:id="author-7"><persName><forename type="first">Jose M</forename><surname>Bras</surname></persName><affiliation>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</affiliation></author><author xml:id="author-8"><persName><forename type="first">John</forename><surname>Hardy</surname></persName><affiliation>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</affiliation></author><author xml:id="author-9"><persName><forename type="first">Javier</forename><surname>Simon-Sanchez</surname></persName><affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</affiliation><affiliation>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</affiliation></author><author xml:id="author-10"><persName><forename type="first">Peter</forename><surname>Heutink</surname></persName><affiliation>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</affiliation></author><author xml:id="author-11"><persName><forename type="first">Gregor</forename><surname>Kuhlenbäumer</surname></persName><affiliation>Institute of Experimental Medicine, Christian-Albrechts University, Kiel, Germany</affiliation></author><author xml:id="author-12"><persName><forename type="first">Rim</forename><surname>Charfi</surname></persName><affiliation>Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>Faculté de Médecine de Tunis, Université de Tunis El Manar, Centre National de Pharmacovigilance de Tunis, Service de Pharmacologie Clinique, Tunis, Tunisia</affiliation></author><author xml:id="author-13"><persName><forename type="first">Christine</forename><surname>Klein</surname></persName><affiliation>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</affiliation></author><author xml:id="author-14"><persName><forename type="first">Johann</forename><surname>Hagenah</surname></persName><affiliation>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</affiliation></author><author xml:id="author-15"><persName><forename type="first">Thomas</forename><surname>Gasser</surname></persName><affiliation>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><affiliation>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</affiliation></author><author xml:id="author-16"><persName><forename type="first">Isabel</forename><surname>Wurster</surname></persName><affiliation>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><affiliation>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</affiliation></author><author xml:id="author-17"><persName><forename type="first">Suzanne</forename><surname>Lesage</surname></persName><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation></author><author xml:id="author-18"><persName><forename type="first">Delia</forename><surname>Lorenz</surname></persName><affiliation>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</affiliation></author><author xml:id="author-19"><persName><forename type="first">Günther</forename><surname>Deuschl</surname></persName><affiliation>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</affiliation></author><author xml:id="author-20"><persName><forename type="first">Franck</forename><surname>Durif</surname></persName><affiliation>Hôpital Gabriel Montpied, CHU de Grenoble, Department of Neurology, Clermont-Ferrand, France</affiliation></author><author xml:id="author-21"><persName><forename type="first">Pierre</forename><surname>Pollak</surname></persName><affiliation>CHU de Grenoble, Department of Neurology, Grenoble, France</affiliation></author><author xml:id="author-22"><persName><forename type="first">Philippe</forename><surname>Damier</surname></persName><affiliation>CHU de Nantes, Centre d'Investigation Clinique, Nantes, France</affiliation></author><author xml:id="author-23"><persName><forename type="first">François</forename><surname>Tison</surname></persName><affiliation>Hôpital Haut-Lévêque, Department of Neurology, Pessac, France</affiliation></author><author xml:id="author-24"><persName><forename type="first">Alexandra</forename><surname>Durr</surname></persName><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation></author><author xml:id="author-25"><persName><forename type="first">Philippe</forename><surname>Amouyel</surname></persName><affiliation>INSERM, U744, Lille, France</affiliation><affiliation>Institut Pasteur de Lille, Lille, France</affiliation><affiliation>Université Lille-Nord de France, Lille, France</affiliation></author><author xml:id="author-26"><persName><forename type="first">Jean-Charles</forename><surname>Lambert</surname></persName><affiliation>INSERM, U744, Lille, France</affiliation><affiliation>Institut Pasteur de Lille, Lille, France</affiliation><affiliation>Université Lille-Nord de France, Lille, France</affiliation></author><author xml:id="author-27"><persName><forename type="first">Christophe</forename><surname>Tzourio</surname></persName><affiliation>Université Pierre et Marie Curie—Paris 6, CNRS 7225 CRICM, ER4-UPMC Modélisation en recherche clinique, Hôpital Pitié-Salpêtrière, Paris, France</affiliation><affiliation>INSERM UMR_S708, Neuroépidémiologie, Paris, France</affiliation></author><author xml:id="author-28"><persName><forename type="first">Cécilia</forename><surname>Maubaret</surname></persName><affiliation>INSERM U897, Université Bordeaux Ségalen, Bordeaux, France</affiliation></author><author xml:id="author-29"><persName><forename type="first">Fanny</forename><surname>Charbonnier-Beaupel</surname></persName><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation></author><author xml:id="author-30"><persName><forename type="first">Khadija</forename><surname>Tahiri</surname></persName><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation></author><author xml:id="author-31"><persName><forename type="first">Marie</forename><surname>Vidailhet</surname></persName><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>“Movement Disorders and Basal Ganglia: Pathophysiology and experimental Therapeutics”, INSERM, UMR_S975, Paris, France</affiliation></author><author xml:id="author-32"><persName><forename type="first">Maria</forename><surname>Martinez</surname></persName><affiliation>INSERM U1043, CPTP, Toulouse, France</affiliation><affiliation>Paul Sabatier University, Toulouse, France</affiliation></author><author xml:id="author-33"><persName><forename type="first">Alexis</forename><surname>Brice</surname></persName><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation></author><author xml:id="author-34"><persName><forename type="first">Jean-Christophe</forename><surname>Corvol</surname></persName><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation></author><author xml:id="author-35"><persName><forename type="first">Y</forename><surname>Agid</surname></persName></author><author xml:id="author-36"><persName><forename type="first">M</forename><surname>Anheim</surname></persName></author><author xml:id="author-37"><persName><forename type="first">A-M</forename><surname>Bonnet</surname></persName></author><author xml:id="author-38"><persName><forename type="first">M</forename><surname>Borg</surname></persName></author><author xml:id="author-39"><persName><forename type="first">A.</forename><surname>Brice</surname></persName></author><author xml:id="author-40"><persName><forename type="first">E</forename><surname>Broussolle</surname></persName></author><author 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type="first">Daniah</forename><surname>Trabzuni</surname></persName></author><author xml:id="author-170"><persName><forename type="first">Bryan J</forename><surname>Traynor</surname></persName></author><author xml:id="author-171"><persName><forename type="first">G</forename><surname>Uitterlinden</surname></persName></author><author xml:id="author-172"><persName><forename type="first">Jana</forename><surname>Vandrovcova</surname></persName></author><author xml:id="author-173"><persName><forename type="first">Daan</forename><surname>Velseboer</surname></persName></author><author xml:id="author-174"><persName><forename type="first">Marie</forename><surname>Vidailhet</surname></persName></author><author xml:id="author-175"><persName><forename type="first">Damjan</forename><surname>Vukcevic</surname></persName></author><author xml:id="author-176"><persName><forename type="first">Robert</forename><surname>Walker</surname></persName></author><author xml:id="author-177"><persName><forename type="first">Bart</forename><surname>van de Warrenburg</surname></persName></author><author xml:id="author-178"><persName><forename type="first">Michael E</forename><surname>Weale</surname></persName></author><author xml:id="author-179"><persName><forename type="first">Mirdhu</forename><surname>Wickremaratchi</surname></persName></author><author xml:id="author-180"><persName><forename type="first">Nigel</forename><surname>Williams</surname></persName></author><author xml:id="author-181"><persName><forename type="first">Caroline H</forename><surname>Williams-Gray</surname></persName></author><author xml:id="author-182"><persName><forename type="first">Sophie</forename><surname>Winder-Rhodes</surname></persName></author><author xml:id="author-183"><persName><forename type="first">Maria</forename><surname>Martinez</surname></persName></author><author xml:id="author-184"><persName><forename type="first">Peter</forename><surname>Donnelly</surname></persName></author><author xml:id="author-185"><persName><forename type="first">John</forename><surname>Hardy</surname></persName></author><author xml:id="author-186"><persName><forename type="first">Peter</forename><surname>Heutink</surname></persName></author><author xml:id="author-187"><persName><forename type="first">Alexis</forename><surname>Brice</surname></persName></author><author xml:id="author-188"><persName><forename type="first">Thomas</forename><surname>Gasser</surname></persName></author><author xml:id="author-189"><persName><forename type="first">Nicholas W</forename><surname>Wood</surname></persName></author><author xml:id="author-190"><persName><forename type="first">Andrew B</forename><surname>Singleton</surname></persName></author></analytic><monogr><title level="j">Journal of Neurology, Neurosurgery & Psychiatry</title><title level="j" type="abbrev">J Neurol Neurosurg Psychiatry</title><idno type="pISSN">0022-3050</idno><idno type="eISSN">1468-330X</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2013-06"></date><biblScope unit="volume">84</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="666">666</biblScope></imprint></monogr><idno type="istex">01332202B2E3FECDAEE2F34EA137D7ED1671829B</idno><idno type="DOI">10.1136/jnnp-2012-304475</idno><idno type="href">jnnp-84-666.pdf</idno><idno type="ArticleID">jnnp-2012-304475</idno><idno type="PMID">23408064</idno><idno type="local">jnnp;84/6/666</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2013-02-13</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.</p></abstract><textClass><keywords scheme="keyword"><list><head>hwp-journal-coll</head><item><term>Open access</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Movement Disorders</term></item><item><term>Neurogenetics</term></item><item><term>Parkinson's Disease</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2013-02-13">Created</change><change when="2013-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/01332202B2E3FECDAEE2F34EA137D7ED1671829B/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus bmj" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="no"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Archiving and Interchange DTD v2.3 20070202//EN" URI="archivearticle.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">jnnp</journal-id><journal-id journal-id-type="nlm-ta">J Neurol Neurosurg Psychiatry</journal-id><journal-id journal-id-type="publisher-id">jnnp</journal-id><journal-title>Journal of Neurology, Neurosurgery & Psychiatry</journal-title><abbrev-journal-title abbrev-type="publisher">J Neurol Neurosurg Psychiatry</abbrev-journal-title><abbrev-journal-title>J Neurol Neurosurg Psychiatry</abbrev-journal-title><issn pub-type="ppub">0022-3050</issn><issn pub-type="epub">1468-330X</issn><publisher><publisher-name>BMJ Publishing Group Ltd</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">jnnp-2012-304475</article-id><article-id pub-id-type="doi">10.1136/jnnp-2012-304475</article-id><article-id pub-id-type="other">jnnp;84/6/666</article-id><article-id pub-id-type="other">jnnp;jnnp-2012-304475</article-id><article-id pub-id-type="pmid">23408064</article-id><article-id pub-id-type="other">666</article-id><article-id pub-id-type="other">jnnp-2012-304475</article-id><article-categories><subj-group subj-group-type="heading"><subject>Movement disorders</subject></subj-group><subj-group subj-group-type="hwp-journal-coll"><subject>Open access</subject></subj-group><series-title>Research 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non-byline"><name><surname>Martinez</surname><given-names>Maria</given-names></name></contrib><contrib contrib-type="author non-byline"><name><surname>Donnelly</surname><given-names>Peter</given-names></name></contrib><contrib contrib-type="author non-byline"><name><surname>Hardy</surname><given-names>John</given-names></name></contrib><contrib contrib-type="author non-byline"><name><surname>Heutink</surname><given-names>Peter</given-names></name></contrib><contrib contrib-type="author non-byline"><name><surname>Brice</surname><given-names>Alexis</given-names></name></contrib><contrib contrib-type="author non-byline"><name><surname>Gasser</surname><given-names>Thomas</given-names></name></contrib><contrib contrib-type="author non-byline"><name><surname>Wood</surname><given-names>Nicholas W</given-names></name></contrib><contrib contrib-type="author non-byline"><name><surname>Singleton</surname><given-names>Andrew B</given-names></name></contrib></contrib-group><aff id="af1"><label>1</label><institution>INSERM, UMR_S975</institution>, <addr-line>CR-ICM, Paris</addr-line>, <country>France</country></aff><aff id="af2"><label>2</label><institution>UPMC University Paris 06, UMR_S975</institution>, <addr-line>CR-ICM, Pitié-Salpêtrière Hospital, Paris</addr-line>, <country>France</country></aff><aff id="af3"><label>3</label><institution>CNRS UMR 7225</institution>, <addr-line>CR-ICM, Pitié-Salpêtrière Hospital, Paris</addr-line>, <country>France</country></aff><aff id="af4"><label>4</label><addr-line>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique</addr-line>, <institution>Hôpital de la Pitié-Salpêtrière</institution>, <addr-line>Paris</addr-line>, <country>France</country></aff><aff id="af5"><label>5</label><institution>INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière</institution>, <addr-line>Paris</addr-line>, <country>France</country></aff><aff id="af6"><label>6</label><addr-line>Assistance Publique Hôpitaux de Paris, Department of Neurology</addr-line>, <institution>Hôpital de la Pitié-Salpêtrière</institution>, <addr-line>Paris</addr-line>, <country>France</country></aff><aff id="af7"><label>7</label><addr-line>Department of Neurology</addr-line>, <institution>University Hospital Würzburg</institution>, <addr-line>Würzburg</addr-line>, <country>Germany</country></aff><aff id="af8"><label>8</label><addr-line>Assistance Publique Hôpitaux de Paris, Department of Biostatistics</addr-line>, <institution>Hôpital de la Pitié-Salpêtrière</institution>, <addr-line>Paris</addr-line>, <country>France</country></aff><aff id="af9"><label>9</label><addr-line>Laboratory of Neurogenetics</addr-line>, <institution>National Institute on Aging, National Institutes of Health</institution>, <addr-line>Bethesda Maryland</addr-line>, <country>USA</country></aff><aff id="af10"><label>10</label><institution>INSERM U1043, CPTP</institution>, <addr-line>Toulouse</addr-line>, <country>France</country></aff><aff id="af11"><label>11</label><institution>Paul Sabatier University</institution>, <addr-line>Toulouse</addr-line>, <country>France</country></aff><aff id="af12"><label>12</label><addr-line>Department of Molecular Neuroscience</addr-line>, <institution>UCL Institute of Neurology</institution>, <addr-line>London</addr-line>, <country>UK</country></aff><aff id="af13"><label>13</label><addr-line>Department of Clinical Genetics Section of Medical Genomics</addr-line>, <institution>VU Medical Center</institution>, <addr-line>Amsterdam</addr-line>, <country>Netherlands</country></aff><aff id="af14"><label>14</label><institution>Institute of Experimental Medicine, Christian-Albrechts University</institution>, <addr-line>Kiel</addr-line>, <country>Germany</country></aff><aff id="af15"><label>15</label><addr-line>Assistance Publique Hôpitaux de Paris, Department of Pharmacology</addr-line>, <institution>Hôpital de la Pitié-Salpêtrière</institution>, <addr-line>Paris</addr-line>, <country>France</country></aff><aff id="af16"><label>16</label><addr-line>Faculté de Médecine de Tunis</addr-line>, <institution>Université de Tunis El Manar</institution>, <institution>Centre National de Pharmacovigilance de Tunis, Service de Pharmacologie Clinique</institution>, <addr-line>Tunis</addr-line>, <country>Tunisia</country></aff><aff id="af17"><label>17</label><addr-line>Institute of Neurogenetics</addr-line>, <institution>University of Lübeck</institution>, <addr-line>Lübeck</addr-line>, <country>Germany</country></aff><aff id="af18"><label>18</label><addr-line>Department of Neurodegenerative Diseases</addr-line>, <institution>Hertie-Institute for Clinical Brain Research, University of Tübingen</institution>, <addr-line>Tübingen</addr-line>, <country>Germany</country></aff><aff id="af19"><label>19</label><addr-line>Department of Neurodegenerative Diseases</addr-line>, <institution>German Center for Neurodegenerative Diseases (DZNE)</institution>, <addr-line>Tübingen</addr-line>, <country>Germany</country></aff><aff id="af20"><label>20</label><addr-line>Department of Neurology</addr-line>, <institution>UKS-H, Campus Kiel; Christian-Albrechts-University</institution>, <addr-line>Kiel</addr-line>, <country>Germany</country></aff><aff id="af21"><label>21</label><addr-line>Hôpital Gabriel Montpied, CHU de Grenoble, Department of Neurology</addr-line>, <addr-line>Clermont-Ferrand</addr-line>, <country>France</country></aff><aff id="af22"><label>22</label><addr-line>CHU de Grenoble, Department of Neurology</addr-line>, <addr-line>Grenoble</addr-line>, <country>France</country></aff><aff id="af23"><label>23</label><addr-line>CHU de Nantes, Centre d'Investigation Clinique</addr-line>, <addr-line>Nantes</addr-line>, <country>France</country></aff><aff id="af24"><label>24</label> <addr-line>Hôpital Haut-Lévêque, Department of Neurology</addr-line>, <addr-line>Pessac</addr-line>, <country>France</country></aff><aff id="af25"><label>25</label><institution>INSERM, U744</institution>, <addr-line>Lille</addr-line>, <country>France</country></aff><aff id="af26"><label>26</label><institution>Institut Pasteur de Lille</institution>, <addr-line>Lille</addr-line>, <country>France</country></aff><aff id="af27"><label>27</label><institution>Université Lille-Nord de France</institution>, <addr-line>Lille</addr-line>, <country>France</country></aff><aff id="af28"><label>28</label><institution>Université Pierre et Marie Curie—Paris 6, CNRS 7225 CRICM, ER4-UPMC Modélisation en recherche clinique, Hôpital Pitié-Salpêtrière</institution>, <addr-line>Paris</addr-line>, <country>France</country></aff><aff id="af29"><label>29</label><addr-line>INSERM UMR_S708, Neuroépidémiologie</addr-line>, <institution>Paris, France</institution></aff><aff id="af30"><label>30</label><institution>INSERM U897, Université Bordeaux Ségalen</institution>, <addr-line>Bordeaux</addr-line>, <country>France</country></aff><aff id="af31"><label>31</label><addr-line>“Movement Disorders and Basal Ganglia: Pathophysiology and experimental Therapeutics”</addr-line>, <institution>INSERM, UMR_S975</institution>, <addr-line>Paris</addr-line>, <country>France</country></aff><author-notes><corresp><label>Correspondence to</label> Dr Jean-Christophe Corvol, Centre d'Investigation Clinique, Institut du Cerveau et de la Moelle épinière, Hôpital de la Pitié-Salpêtrière, 47 boulevard de l'Hôpital, Paris 75651 Cedex 13, France; <email>jean-christophe.corvol@psl.aphp.fr</email>. </corresp></author-notes><pub-date pub-type="ppub"><month>6</month><year>2013</year></pub-date><pub-date pub-type="epub-original"><day>13</day><month>2</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>13</day><month>2</month><year>2013</year></pub-date><volume>84</volume><volume-id pub-id-type="other">84</volume-id><volume-id pub-id-type="other">84</volume-id><issue>6</issue><issue-id pub-id-type="other">jnnp;84/6</issue-id><issue-id pub-id-type="other">6</issue-id><issue-id pub-id-type="other">84/6</issue-id><fpage>666</fpage><history><date date-type="received"><day>5</day><month>11</month><year>2012</year></date><date date-type="rev-recd"><day>4</day><month>1</month><year>2013</year></date><date date-type="accepted"><day>7</day><month>1</month><year>2013</year></date></history><permissions><copyright-statement>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</copyright-statement><copyright-year>2013</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/legalcode">http://creativecommons.org/licenses/by-nc/3.0/legalcode</ext-link></p></license></permissions><self-uri content-type="pdf" xlink:role="full-text" xlink:href="jnnp-84-666.pdf"></self-uri><abstract><p>The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the <italic>COMT</italic> gene (<italic>rs4680</italic>) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The <italic>rs4680</italic> was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with <italic>COMT</italic> genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. <italic>COMT</italic> genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.</p></abstract><kwd-group><kwd>Movement Disorders</kwd><kwd>Neurogenetics</kwd><kwd>Parkinson's Disease</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism</title><partName>Research paper</partName></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism</title><partName>Research paper</partName></titleInfo><name type="corporate"><namePart>French Parkinson's Disease Genetics Study Group and the International Parkinson's Disease Genomics Consortium (IPDGC)</namePart></name><name type="personal"><namePart type="given">Stephan</namePart><namePart type="family">Klebe</namePart><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>Department of Neurology, University Hospital Würzburg, Würzburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean-Louis</namePart><namePart type="family">Golmard</namePart><affiliation>Assistance Publique Hôpitaux de Paris, Department of Biostatistics, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael A</namePart><namePart type="family">Nalls</namePart><affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mohamad</namePart><namePart type="family">Saad</namePart><affiliation>INSERM U1043, CPTP, Toulouse, France</affiliation><affiliation>Paul Sabatier University, Toulouse, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andrew B</namePart><namePart type="family">Singleton</namePart><affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jose M</namePart><namePart type="family">Bras</namePart><affiliation>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John</namePart><namePart type="family">Hardy</namePart><affiliation>Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Javier</namePart><namePart type="family">Simon-Sanchez</namePart><affiliation>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA</affiliation><affiliation>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Heutink</namePart><affiliation>Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gregor</namePart><namePart type="family">Kuhlenbäumer</namePart><affiliation>Institute of Experimental Medicine, Christian-Albrechts University, Kiel, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rim</namePart><namePart type="family">Charfi</namePart><affiliation>Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>Faculté de Médecine de Tunis, Université de Tunis El Manar, Centre National de Pharmacovigilance de Tunis, Service de Pharmacologie Clinique, Tunis, Tunisia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christine</namePart><namePart type="family">Klein</namePart><affiliation>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Johann</namePart><namePart type="family">Hagenah</namePart><affiliation>Institute of Neurogenetics, University of Lübeck, Lübeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Gasser</namePart><affiliation>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><affiliation>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Isabel</namePart><namePart type="family">Wurster</namePart><affiliation>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><affiliation>Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Suzanne</namePart><namePart type="family">Lesage</namePart><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Delia</namePart><namePart type="family">Lorenz</namePart><affiliation>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Günther</namePart><namePart type="family">Deuschl</namePart><affiliation>Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Franck</namePart><namePart type="family">Durif</namePart><affiliation>Hôpital Gabriel Montpied, CHU de Grenoble, Department of Neurology, Clermont-Ferrand, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Pierre</namePart><namePart type="family">Pollak</namePart><affiliation>CHU de Grenoble, Department of Neurology, Grenoble, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Philippe</namePart><namePart type="family">Damier</namePart><affiliation>CHU de Nantes, Centre d'Investigation Clinique, Nantes, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">François</namePart><namePart type="family">Tison</namePart><affiliation>Hôpital Haut-Lévêque, Department of Neurology, Pessac, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexandra</namePart><namePart type="family">Durr</namePart><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Philippe</namePart><namePart type="family">Amouyel</namePart><affiliation>INSERM, U744, Lille, France</affiliation><affiliation>Institut Pasteur de Lille, Lille, France</affiliation><affiliation>Université Lille-Nord de France, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean-Charles</namePart><namePart type="family">Lambert</namePart><affiliation>INSERM, U744, Lille, France</affiliation><affiliation>Institut Pasteur de Lille, Lille, France</affiliation><affiliation>Université Lille-Nord de France, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christophe</namePart><namePart type="family">Tzourio</namePart><affiliation>Université Pierre et Marie Curie—Paris 6, CNRS 7225 CRICM, ER4-UPMC Modélisation en recherche clinique, Hôpital Pitié-Salpêtrière, Paris, France</affiliation><affiliation>INSERM UMR_S708, Neuroépidémiologie, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Cécilia</namePart><namePart type="family">Maubaret</namePart><affiliation>INSERM U897, Université Bordeaux Ségalen, Bordeaux, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fanny</namePart><namePart type="family">Charbonnier-Beaupel</namePart><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Khadija</namePart><namePart type="family">Tahiri</namePart><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marie</namePart><namePart type="family">Vidailhet</namePart><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France</affiliation><affiliation>“Movement Disorders and Basal Ganglia: Pathophysiology and experimental Therapeutics”, INSERM, UMR_S975, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Maria</namePart><namePart type="family">Martinez</namePart><affiliation>INSERM U1043, CPTP, Toulouse, France</affiliation><affiliation>Paul Sabatier University, Toulouse, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexis</namePart><namePart type="family">Brice</namePart><affiliation>INSERM, UMR_S975, CR-ICM, Paris, France</affiliation><affiliation>UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France</affiliation><affiliation>Assitance Publique Hôpitaux de Paris, 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type="personal"><namePart type="given">Bart</namePart><namePart type="family">van de Warrenburg</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Michael E</namePart><namePart type="family">Weale</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Mirdhu</namePart><namePart type="family">Wickremaratchi</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Nigel</namePart><namePart type="family">Williams</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Caroline H</namePart><namePart type="family">Williams-Gray</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Sophie</namePart><namePart type="family">Winder-Rhodes</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Maria</namePart><namePart type="family">Martinez</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Donnelly</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">John</namePart><namePart type="family">Hardy</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Heutink</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Alexis</namePart><namePart type="family">Brice</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Gasser</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Nicholas W</namePart><namePart type="family">Wood</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><name type="personal"><namePart type="given">Andrew B</namePart><namePart type="family">Singleton</namePart><role><roleTerm type="text">author non-byline</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><genre>hwp-journal-coll</genre><topic>Open access</topic></subject><originInfo><publisher>BMJ Publishing Group Ltd</publisher><dateIssued encoding="w3cdtf">2013-06</dateIssued><dateCreated encoding="w3cdtf">2013-02-13</dateCreated><copyrightDate encoding="w3cdtf">2013</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.</abstract><subject><genre>keywords</genre><topic>Movement Disorders</topic><topic>Neurogenetics</topic><topic>Parkinson's Disease</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Neurology, Neurosurgery & Psychiatry</title></titleInfo><titleInfo type="abbreviated"><title>J Neurol Neurosurg Psychiatry</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0022-3050</identifier><identifier type="eISSN">1468-330X</identifier><identifier type="PublisherID">jnnp</identifier><identifier type="PublisherID-hwp">jnnp</identifier><identifier type="PublisherID-nlm-ta">J Neurol Neurosurg Psychiatry</identifier><part><date>2013</date><detail type="volume"><caption>vol.</caption><number>84</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>666</start></extent></part></relatedItem><identifier type="istex">01332202B2E3FECDAEE2F34EA137D7ED1671829B</identifier><identifier type="DOI">10.1136/jnnp-2012-304475</identifier><identifier type="href">jnnp-84-666.pdf</identifier><identifier type="ArticleID">jnnp-2012-304475</identifier><identifier type="PMID">23408064</identifier><identifier type="local">jnnp;84/6/666</identifier><accessCondition type="use and reproduction" contentType="open-access">This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode</accessCondition><recordInfo><recordContentSource>BMJ</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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