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Original Investigation
July 2016

Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis

Author Affiliations
  • 1Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King’s College London, London, England
  • 2Department of Neurology and Laboratory of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, Milano, Italy
  • 3Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Ireland
  • 4Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
  • 5Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
  • 6Department of Pathophysiology and Tranplantation, Dino Ferrari Center, Università degli Studi di Milano, Milano, Italy
  • 7Rita Levi Montalcini Department of Neuroscience, ALS (Amyotrophic Lateral Sclerosis) Centre, University of Torino, Turin, Italy
  • 8Azienda Ospedaliera Città della Salute e della Scienza, Torino, Italy
  • 9Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • 10Department of Neurosciences, University of Padova, Padua, Italy
  • 11Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, A. Avogadro University, Novara, Italy
  • 12Department of Biostatistics, IoPPN, King’s College London, London, England
  • 13Neurologic Unit, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
  • 14Laboratory of Experimental Neurobiology, IRCCS C. Mondino National Institute of Neurology Foundation, Pavia, Italy
  • 15Department of Neurology, Emory University, Atlanta, Georgia
  • 16National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, IoPPN, King’s College London, London, England
  • 17Department of Biostatistics, IoPPN, King’s College London, London, England
  • 18NIHR Biomedical Research Unit in Dementia, King’s College London, London, England
  • 19Département des Maladies du Système Nerveux, Assistance Publique–Hôpitaux de Paris, Réseau SLA (Sclérose Latérale) Île de France, Hôpital Pitié-Salpêtrière, Paris, France
  • 20Institut National de la Santé et de la Recherche Medicale Unité Mixte de Recherché–788 and University of Paris 11, Bicetre Hospital, Paris, France
  • 21School of Clinical and Experimental Medicine, College of Medicine and Dentistry, University of Birmingham, Birmingham, England
  • 22Neurosciences Division, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, England
  • 23Academic Neurology Unit, Department of Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, England
  • 24Section of Neurology, Division of Medicine, Brighton and Sussex Medical School, Trafford Centre for Biomedical Research, University of Sussex, East Sussex, England
  • 25Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
  • 26Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
  • 27ALS Center Department of Neurology, Maggiore della Carità University Hospital, Novara, Italy
  • 28Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
  • 29Department of Neurosciences, Experimental Neurology, Flanders Instititue for Biotechnology, Vesalius Research Center, Laboratory of Neurobiology, KU Leuven–University of Leuven, Leuven, Belgium
  • 30Department of Neurology, University Hospitals Leuven, Leuven, Belgium
  • 31Department of Neurology, University of Massachusetts Medical School, Worcester
  • 32IoPPN Genomics and Biomarker Core, Translational Genetics Group, Medical Research Council Social, Genetic and Developmental Psychiatry Centre, King’s College London, London, England
  • 33Department of Medical and Molecular Genetics, King’s College London, London, England
JAMA Neurol. 2016;73(7):812-820. doi:10.1001/jamaneurol.2016.1114

Importance  Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset.

Objective  To identify gene variants influencing survival in ALS.

Design, Setting, and Participants  This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015.

Main Outcomes and Measures  Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis.

Results  Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10−9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10−8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10−9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10−8), corresponding to a 4-month reduction in survival compared with TT carriers.

Conclusions and Relevance  This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.