title: Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.
abstract: 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.
  
  
  
  To identify gene variants influencing survival in ALS.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, England.
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authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, England.
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authors.affiliation: Department of Neurology and Laboratory of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, Milano, Italy.
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authors.affiliation: 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.
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authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, England.
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authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
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authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, England.
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authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, England.
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authors.affiliation: 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.
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authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, England.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, England.
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mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D015534:Trans-Activators / Q000235:genetics*
chemical_list: C487554:CAMTA1 protein, human; D002135:Calcium-Binding Proteins; D015534:Trans-Activators