Isabella Fogh1, Kuang Lin1, Cinzia Tiloca2, James Rooney3, Cinzia Gellera4, Frank P Diekstra5, Antonia Ratti6, Aleksey Shatunov1, Michael A van Es5, Petroula Proitsi1, Ashley Jones1, William Sproviero1, Adriano Chiò7, Russell Lewis McLaughlin8, Gianni Sorarù9, Lucia Corrado10, Daniel Stahl11, Roberto Del Bo12, Cristina Cereda13, Barbara Castellotti4, Jonathan D Glass14, Steven Newhouse15, Richard Dobson16, Bradley N Smith1, Simon Topp1, Wouter van Rheenen5, Vincent Meininger17, Judith Melki18, Karen E Morrison19, Pamela J Shaw20, P Nigel Leigh21, Peter M Andersen22, Giacomo P Comi12, Nicola Ticozzi6, Letizia Mazzini23, Sandra D'Alfonso10, Bryan J Traynor24, Philip Van Damme25, Wim Robberecht26, Robert H Brown27, John E Landers27, Orla Hardiman8, Cathryn M Lewis28, Leonard H van den Berg5, Christopher E Shaw1, Jan H Veldink5, Vincenzo Silani6, Ammar Al-Chalabi1, John Powell1. 1. Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, England. 2. Department of Neurology and Laboratory of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, Milano, Italy. 3. Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Ireland. 4. Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. 5. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. 6. Department of Neurology and Laboratory of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, Milano, Italy6Department of Pathophysiology and Tranplantation, Dino Ferrari Center, Università degli Studi d. 7. Rita Levi Montalcini Department of Neuroscience, ALS (Amyotrophic Lateral Sclerosis) Centre, University of Torino, Turin, Italy8Azienda Ospedaliera Città della Salute e della Scienza, Torino, Italy. 8. Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. 9. Department of Neurosciences, University of Padova, Padua, Italy. 10. Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, A. Avogadro University, Novara, Italy. 11. Department of Biostatistics, IoPPN, King's College London, London, England. 12. Neurologic Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 13. Laboratory of Experimental Neurobiology, IRCCS C. Mondino National Institute of Neurology Foundation, Pavia, Italy. 14. Department of Neurology, Emory University, Atlanta, Georgia. 15. National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, IoPPN, King's College London, London, England17Department of Biostatistics, IoPPN, King's College London, London, England. 16. National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, IoPPN, King's College London, London, England18NIHR Biomedical Research Unit in Dementia, King's College London, London, England. 17. Département des Maladies du Système Nerveux, Assistance Publique-Hôpitaux de Paris, Réseau SLA (Sclérose Latérale) Île de France, Hôpital Pitié-Salpêtrière, Paris, France. 18. Institut National de la Santé et de la Recherche Medicale Unité Mixte de Recherché-788 and University of Paris 11, Bicetre Hospital, Paris, France. 19. School of Clinical and Experimental Medicine, College of Medicine and Dentistry, University of Birmingham, Birmingham, England22Neurosciences Division, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, England. 20. Academic Neurology Unit, Department of Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, England. 21. Section of Neurology, Division of Medicine, Brighton and Sussex Medical School, Trafford Centre for Biomedical Research, University of Sussex, East Sussex, England. 22. Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany26Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden. 23. Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, A. Avogadro University, Novara, Italy27ALS Center Department of Neurology, Maggiore della Carità University Hospital, Novara, Italy. 24. Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland. 25. Department of Neurosciences, Experimental Neurology, Flanders Instititue for Biotechnology, Vesalius Research Center, Laboratory of Neurobiology, KU Leuven-University of Leuven, Leuven, Belgium30Department of Neurology, University Hospitals Leuven, Leuven. 26. Department of Neurosciences, Experimental Neurology, Flanders Instititue for Biotechnology, Vesalius Research Center, Laboratory of Neurobiology, KU Leuven-University of Leuven, Leuven, Belgium. 27. Department of Neurology, University of Massachusetts Medical School, Worcester. 28. IoPPN Genomics and Biomarker Core, Translational Genetics Group, Medical Research Council Social, Genetic and Developmental Psychiatry Centre, King's College London, London, England33Department of Medical and Molecular Genetics, King's College London, Lon.
Abstract
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.
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.
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