title: TREM2 R47H variant and risk of essential tremor: a cross-sectional international multicenter study.
abstract: BACKGROUND
  Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET.
  
  
  METHODS
  This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency.
  
  
  RESULTS
  There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203-29.626; p = 0.042), but it was not replicated in other populations.
  
  
  CONCLUSIONS
  These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed.
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain; Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ortega-Cubero
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Lorenzo-Betancor
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Lorenzo
authors.affiliation: Department of Pharmacology, University of Extremadura, Cáceres, Spain.
authors.forename: José A G
authors.initials: JA
authors.lastname: Agúndez
authors.affiliation: Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain.
authors.forename: Félix J
authors.initials: FJ
authors.lastname: Jiménez-Jiménez
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department for Neurodegenerative Diseases (DZNE), Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Wurster
authors.affiliation: Department for Neurodegenerative Diseases (DZNE), Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Mielke
authors.affiliation: Department of Neurology, Chushang Show-Chwan Hospital, Nantou, Taiwan; Department of Neurology, Chung-Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Juei-Jueng
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Department of Neurology, Son Espases University Hospital, Mallorca, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Coria
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain; Neurology Department, Institut d'Investigacions Biomediques Sant Pau, Hospital de Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimon
authors.affiliation: Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clinic de Neurociencies, Hospital Clinic de Barcelona, CIBERNED, Barcelona, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Ezquerra
authors.affiliation: Department of Neurology, San Gerardo Hospital, Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Brighina
authors.affiliation: Section of Neuroimaging, Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Annesi
authors.affiliation: Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain.
authors.forename: Hortensia
authors.initials: H
authors.lastname: Alonso-Navarro
authors.affiliation: Department of Biochemistry of Molecular Biology, University of Extremadura, Cáceres, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martin
authors.affiliation: Movement Disorders Unit, Department of Neurology, Hospital de Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Gironell
authors.affiliation: Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clinic de Neurociencies, Hospital Clinic de Barcelona, CIBERNED, Barcelona, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Marti
authors.affiliation: Department of Neurology, Chushang Show-Chwan Hospital, Nantou, Taiwan.
authors.forename: Kuo-Chu
authors.initials: KC
authors.lastname: Yueh
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Department for Neurodegenerative Diseases (DZNE), Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Department for Neurodegenerative Diseases (DZNE), Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.affiliation: Department for Neurodegenerative Diseases (DZNE), Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Luxembourg Center for Systems Biomedicine, University of Luxembourg and Centre Hospitalier de Luxembourg, Luxembourg.
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.affiliation: Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain; Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pastor
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain; Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain; Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain. Electronic address: pastorpau@gmail.com.
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000235:genetics*; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D020329:Essential Tremor / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006639:Histidine / Q000235:genetics*; D006801:Humans; D007391:International Cooperation; D007558:Italy; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009656:North America; D011971:Receptors, Immunologic / Q000235:genetics*; D012307:Risk Factors; D013030:Spain; D013624:Taiwan; D055815:Young Adult
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; D006639:Histidine; D001120:Arginine
keywords: Essential tremor; Genetics; Risk; TREM2; p.R47H