ATXN2 trinucleotide repeat length correlates with risk of ALS

William Sproviero; Aleksey Shatunov; Daniel Stahl; Maryam Shoai; Wouter van Rheenen; Ashley R Jones; Safa Al-Sarraj; Peter M Andersen; Nancy M Bonini; Francesca L Conforti; Philip Van Damme; Hussein Daoud; Maria Del Mar Amador; Isabella Fogh; Monica Forzan; Ben Gaastra; Cinzia Gellera; Aaron D Gitler; John Hardy; Pietro Fratta; Vincenzo La Bella; Isabelle Le Ber; Tim Van Langenhove; Serena Lattante; Yi-Chung Lee; Andrea Malaspina; Vincent Meininger; Stéphanie Millecamps; Richard Orrell; Rosa Rademakers; Wim Robberecht; Guy Rouleau; Owen A Ross; Francois Salachas; Katie Sidle; Bradley N Smith; Bing-Wen Soong; Gianni Sorarù; Giovanni Stevanin; Edor Kabashi; Claire Troakes; Christine van Broeckhoven; Jan H Veldink; Leonard H van den Berg; Christopher E Shaw; John F Powell; Ammar Al-Chalabi

doi:10.1016/j.neurobiolaging.2016.11.010

ATXN2 trinucleotide repeat length correlates with risk of ALS

Neurobiol Aging. 2017 Mar:51:178.e1-178.e9. doi: 10.1016/j.neurobiolaging.2016.11.010. Epub 2016 Nov 24.

Authors

William Sproviero¹, Aleksey Shatunov¹, Daniel Stahl², Maryam Shoai³, Wouter van Rheenen⁴, Ashley R Jones¹, Safa Al-Sarraj⁵, Peter M Andersen⁶, Nancy M Bonini⁷, Francesca L Conforti⁸, Philip Van Damme⁹, Hussein Daoud¹⁰, Maria Del Mar Amador¹¹, Isabella Fogh¹, Monica Forzan¹², Ben Gaastra¹, Cinzia Gellera¹³, Aaron D Gitler¹⁴, John Hardy³, Pietro Fratta¹⁵, Vincenzo La Bella¹⁶, Isabelle Le Ber¹⁷, Tim Van Langenhove¹⁸, Serena Lattante¹⁹, Yi-Chung Lee²⁰, Andrea Malaspina²¹, Vincent Meininger²², Stéphanie Millecamps¹⁹, Richard Orrell²³, Rosa Rademakers²⁴, Wim Robberecht²⁵, Guy Rouleau¹⁰, Owen A Ross²⁴, Francois Salachas²⁶, Katie Sidle³, Bradley N Smith¹, Bing-Wen Soong²⁰, Gianni Sorarù²⁷, Giovanni Stevanin²⁸, Edor Kabashi¹⁹, Claire Troakes¹, Christine van Broeckhoven²⁹, Jan H Veldink⁴, Leonard H van den Berg⁴, Christopher E Shaw¹, John F Powell¹, Ammar Al-Chalabi³⁰

Affiliations

¹ Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
² Department of Biostatistics, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
³ Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK.
⁴ Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands.
⁵ Department of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, UK.
⁶ Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
⁷ Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Institute of Neurological Sciences, National Research Council, Cosenza, Italy.
⁹ Neurology Department, University Hospitals Leuven, Leuven, Belgium; Vesalius Research Center, VIB, Leuven, Belgium; Disease (LIND), KU Leuven - University of Leuven, Leuven, Belgium.
¹⁰ Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
¹¹ Department of Nervous System Diseases, ALS Paris ALS Center for Rare Diseases, Groupe Hospitalier Pitié Salpêtrière, APHP, Paris, France.
¹² Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
¹³ Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
¹⁴ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, UK.
¹⁶ ALS Clinical Research Center, Bio. Ne. C., University of Palermo, Palermo, Italy.
¹⁷ 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.
¹⁸ 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.
¹⁹ Institut du Cerveau et de la Moelle épinière (ICM), Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS1127, Paris, France.
²⁰ 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.
²¹ 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.
²² 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.
²³ Department of Clinical Neuroscience, University College London (UCL) Institute of Neurology, London, UK.
²⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
²⁵ Vesalius Research Center, VIB, Leuven, Belgium; Disease (LIND), KU Leuven - University of Leuven, Leuven, Belgium.
²⁶ 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.
²⁷ Department of Neurosciences, University of Padova, Padova, Italy.
²⁸ 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.
²⁹ Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Insititute Born-Bunge, University of Antwerp, Antwerp, Belgium.
³⁰ Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK. Electronic address: [email protected].

PMID: 28017481
PMCID: PMC5302215
DOI: 10.1016/j.neurobiolaging.2016.11.010

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.

Keywords: ALS; ATXN2; Age of onset; Amyotrophic lateral sclerosis; CAG; Expansion; Exponential risk; Intermediate expansion; Risk; SCA2; Trinucleotide repeat; Triplet.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Age of Onset
Alleles
Amyotrophic Lateral Sclerosis / genetics*
Ataxin-2 / genetics*
Case-Control Studies
Female
Genetic Association Studies*
Humans
Male
Risk
Trinucleotide Repeat Expansion / genetics*
Trinucleotide Repeats / genetics*

Substances

ATXN2 protein, human
Ataxin-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding