title: ATXN2 trinucleotide repeat length correlates with risk of ALS.
abstract: We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10-18), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R2= 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: William
authors.initials: W
authors.lastname: Sproviero
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Shatunov
authors.affiliation: Department of Biostatistics, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stahl
authors.affiliation: Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Shoai
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: van Rheenen
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Jones
authors.affiliation: Department of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
authors.affiliation: Institute of Neurological Sciences, National Research Council, Cosenza, Italy.
authors.forename: Francesca L
authors.initials: FL
authors.lastname: Conforti
authors.affiliation: Neurology Department, University Hospitals Leuven, Leuven, Belgium; Vesalius Research Center, VIB, Leuven, Belgium; Disease (LIND), KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Hussein
authors.initials: H
authors.lastname: Daoud
authors.affiliation: Department of Nervous System Diseases, ALS Paris ALS Center for Rare Diseases, Groupe Hospitalier Pitié Salpêtrière, APHP, Paris, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Del Mar Amador
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: Isabella
authors.initials: I
authors.lastname: Fogh
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Forzan
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Gaastra
authors.affiliation: Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Gellera
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.affiliation: Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fratta
authors.affiliation: ALS Clinical Research Center, Bio. Ne. C., University of Palermo, Palermo, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: La Bella
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS1127, Paris, France; AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Centre de Référence des Démences Rares, Departement de Neurologie, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Insititute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Van Langenhove
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS1127, Paris, France.
authors.forename: Serena
authors.initials: S
authors.lastname: Lattante
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Lee
authors.affiliation: North-East London and Essex MND Care Centre - Neuroscience and Trauma Centre, Blizard, Institute of Cell and Molecular Medicine, Barts & the London School of Medicine & Dentistry, Barts Health NHS Trust, London, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Malaspina
authors.affiliation: Hôpital de la Pitié-Salpêtrière, institut de recherche translationnelle en neurosciences (A-ICM), Paris, France; Hôpital de la Pitié-Salpêtrière, réseau SLA IdF, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS1127, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Millecamps
authors.affiliation: Department of Clinical Neuroscience, University College London (UCL) Institute of Neurology, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Orrell
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium; Disease (LIND), KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Rouleau
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department of Nervous System Diseases, ALS Paris ALS Center for Rare Diseases, Groupe Hospitalier Pitié Salpêtrière, APHP, Paris, France; Institut du Cerveau et de la Moelle épinière (ICM), Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS1127, Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Salachas
authors.affiliation: Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Sidle
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.affiliation: Department of Neurosciences, University of Padova, Padova, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Sorarù
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS1127, Paris, France; Neurogenetics team, Ecole Pratique des Hautes Etudes, Paris, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS1127, Paris, France.
authors.forename: Edor
authors.initials: E
authors.lastname: Kabashi
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Insititute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: van Broeckhoven
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK. Electronic address: ammar.al-chalabi@kcl.ac.uk.
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000067698:Ataxin-2 / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D012306:Risk; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: C000593752:ATXN2 protein, human; D000067698:Ataxin-2
keywords: ALS; ATXN2; Age of onset; Amyotrophic lateral sclerosis; CAG; Expansion; Exponential risk; Intermediate expansion; Risk; SCA2; Trinucleotide repeat; Triplet