title: Genome-wide association study in essential tremor identifies three new loci.
abstract: We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
authors: 1 Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.
authors: Stefanie H
authors: SH
authors: Müller
authors: 2 Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Saguenay, Canada.|3 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Canada.
authors: Simon L
authors: SL
authors: Girard
authors: 1 Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.
authors: Franziska
authors: F
authors: Hopfner
authors: 3 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Canada.|4 Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors: Nancy D
authors: ND
authors: Merner
authors: 3 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Canada.
authors: Cynthia V
authors: CV
authors: Bourassa
authors: 5 University Children's Hospital, University of Würzburg, Würzburg, Germany.
authors: Delia
authors: D
authors: Lorenz
authors: 6 Department of Pathology and Cell Biology, Taub Institute, Columbia University, New York City, NY, USA.
authors: Lorraine N
authors: LN
authors: Clark
authors: 7 Institute of Epidemiology, Christian-Albrechts University Kiel and Biobank POPGEN, Kiel, Germany.
authors: Lukas
authors: L
authors: Tittmann
authors: 8 Department of Neuroscience and Neurology, Mayo Clinic, Florida, USA.
authors: Alexandra I
authors: AI
authors: Soto-Ortolaza
authors: 9 Department of Neurology, University Hospital Würzburg, Würzburg, Germany.|10 Department of Neurology, University Hospital Freiburg, Freiburg im Breisgau, Germany.
authors: Stephan
authors: S
authors: Klebe
authors: 11 NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
authors: Mark
authors: M
authors: Hallett
authors: 1 Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.|12 Department of Neurology, Ludwig-Maximilians-Universität München, Munich Germany.
authors: Susanne A
authors: SA
authors: Schneider
authors: 13 NIAAA/NIH Bethesda MD, USA.
authors: Colin A
authors: CA
authors: Hodgkinson
authors: 7 Institute of Epidemiology, Christian-Albrechts University Kiel and Biobank POPGEN, Kiel, Germany.
authors: Wolfgang
authors: W
authors: Lieb
authors: 8 Department of Neuroscience and Neurology, Mayo Clinic, Florida, USA.
authors: Zbigniew K
authors: ZK
authors: Wszolek
authors: 14 Department of Paediatric Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.
authors: Manuela
authors: M
authors: Pendziwiat
authors: 15 Neurogenetics, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, CIBERNED, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.|16 Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona, Barcelona, Spain.
authors: Oswaldo
authors: O
authors: Lorenzo-Betancor
authors: 17 Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors: Werner
authors: W
authors: Poewe
authors: 15 Neurogenetics, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, CIBERNED, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.|16 Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona, Barcelona, Spain.
authors: Sara
authors: S
authors: Ortega-Cubero
authors: 17 Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors: Klaus
authors: K
authors: Seppi
authors: 18 University of Saskatchewan and Saskatoon Health Region, Saskatoon, SK, Canada.
authors: Alex
authors: A
authors: Rajput
authors: 17 Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors: Anna
authors: A
authors: Hussl
authors: 18 University of Saskatchewan and Saskatoon Health Region, Saskatoon, SK, Canada.
authors: Ali H
authors: AH
authors: Rajput
authors: 1 Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.
authors: Daniela
authors: D
authors: Berg
authors: 3 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Canada.
authors: Patrick A
authors: PA
authors: Dion
authors: 19 Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors: Isabel
authors: I
authors: Wurster
authors: 20 Department of Neurology, Baylor College of Medicine, Houston, TX, USA.|21 Departments of Molecular and Human Genetics and Neuroscience, and Program in Developmental Biology, Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors: Joshua M
authors: JM
authors: Shulman
authors: 19 Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors: Karin
authors: K
authors: Srulijes
authors: 11 NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
authors: Dietrich
authors: D
authors: Haubenberger
authors: 15 Neurogenetics, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, CIBERNED, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.|16 Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona, Barcelona, Spain.
authors: Pau
authors: P
authors: Pastor
authors: 22 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors: Carles
authors: C
authors: Vilariño-Güell
authors: 3 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Canada.|23 Department of Neurology, Montreal General Hospital, Montréal, QC, Canada.
authors: Ronald B
authors: RB
authors: Postuma
authors: 3 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Canada.|24 Departments of Pediatrics, Neurology and Neurosurgery, division of Pediatric Neurology, Montreal Children's Hospital, Montreal, Canada.
authors: Geneviève
authors: G
authors: Bernard
authors: 25 Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|26 Department of Psychosomatic Medicine and Psychotherapy, Klinikum rechts der Isar, Technische Universität, Munich, Germany.
authors: Karl-Heinz
authors: KH
authors: Ladwig
authors: 27 Faculté de Médecine, Université Laval, CHU de Québec (Enfant-Jésus), Québec, QC, Canada.
authors: Nicolas
authors: N
authors: Dupré
authors: 20 Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors: Joseph
authors: J
authors: Jankovic
authors: 28 Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|29 Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Konstantin
authors: K
authors: Strauch
authors: 30 Unité des troubles du mouvement André Barbeau, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors: Michel
authors: M
authors: Panisset
authors: 31 Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.|32 Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, and Munich Cluster for Systems Neurology (Synergy), Munich, Germany.
authors: Juliane
authors: J
authors: Winkelmann
authors: 33 Department of Neurology and Parkinson's and Movement Disorders Center, Virginia Commonwealth University, Richmond VA, USA.
authors: Claudia M
authors: CM
authors: Testa
authors: 25 Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|34 Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors: Eva
authors: E
authors: Reischl
authors: 1 Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.
authors: Kirsten E
authors: KE
authors: Zeuner
authors: 8 Department of Neuroscience and Neurology, Mayo Clinic, Florida, USA.
authors: Owen A
authors: OA
authors: Ross
authors: 35 Center for Neuropathology and Prion Research, University of Munich, 80539 München, Germany.|36 Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
authors: Thomas
authors: T
authors: Arzberger
authors: 30 Unité des troubles du mouvement André Barbeau, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors: Sylvain
authors: S
authors: Chouinard
authors: 1 Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.
authors: Günther
authors: G
authors: Deuschl
authors: 37 Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: Elan D
authors: ED
authors: Louis
authors: 1 Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.
authors: Gregor
authors: G
authors: Kuhlenbäumer
authors: 3 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Canada guy.rouleau@mcgill.ca.
authors: Guy A
authors: GA
authors: Rouleau
mesh_terms: D020329:Essential Tremor / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051178:alpha Catenin / Q000235:genetics*
chemical_list: C441963:CTNNA3 protein, human; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051178:alpha Catenin; D017346:Protein Serine-Threonine Kinases; C551917:STK32B protein, human
keywords: essential tremor; genetics; genome-wide association study; movement disorders; tremor