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Original Investigation |

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

Isabella Fogh, PhD1; Kuang Lin, PhD1; Cinzia Tiloca, PhD2; James Rooney, MD3; Cinzia Gellera, PhD4; Frank P. Diekstra, MD5; Antonia Ratti, PhD2,6; Aleksey Shatunov, PhD1; Michael A. van Es, MD, PhD5; Petroula Proitsi, PhD1; Ashley Jones, PhD1; William Sproviero, PhD1; Adriano Chiò, MD7,8; Russell Lewis McLaughlin, PhD9; Gianni Sorarù, MD, PhD10; Lucia Corrado, PhD11; Daniel Stahl, PhD12; Roberto Del Bo, PhD13; Cristina Cereda, PhD14; Barbara Castellotti, PhD4; Jonathan D. Glass, MD15; Steven Newhouse, PhD16,17; Richard Dobson, PhD16,18; Bradley N. Smith, PhD1; Simon Topp, MSc1; Wouter van Rheenen, MD5; Vincent Meininger, MD, PhD19; Judith Melki, MD, PhD20; Karen E. Morrison, MD21,22; Pamela J. Shaw, MD23; P. Nigel Leigh, MD, PhD24; Peter M. Andersen, MD, DMSc25,26; Giacomo P. Comi, MD13; Nicola Ticozzi, MD2,6; Letizia Mazzini, MD11,27; Sandra D’Alfonso, PhD11; Bryan J. Traynor, MD28; Philip Van Damme, MD, PhD29,30; Wim Robberecht, MD, PhD29; Robert H. Brown, MD, DPhil31; John E. Landers, PhD31; Orla Hardiman, MD, FRCPI9; Cathryn M. Lewis, PhD32,33; Leonard H. van den Berg, MD, PhD5; Christopher E. Shaw, MD1; Jan H. Veldink, MD, PhD5; Vincenzo Silani, MD2,6; Ammar Al-Chalabi, PhD, FRCP1; John Powell, PhD1
[+] 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.
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Published online

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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Figure 1.
Genome-wide Association Study of Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis (ALS)

A, Manhattan plot of the combined (METAL software) Cox proportional hazards regression analysis. The threshold for genome-wide significance after correction for multiple testing was set at P = 5 × 10−8 (horizontal blue line). Loci significantly associated with ALS survival are highlighted in red and labeled according to the corresponding genes. At locus 10q23, the most associated single-nucleotide polymorphism (SNP), rs139550538 (P = 1.87 × 10−9), was moderately rare with a minor allele frequency (MAF) of 0.03, whereas at the 1p36 locus, the 4 SNPs significantly associated (rs2412208 [P = 3.53 × 10−8], rs4584415 [P = 3.68 × 10−8], rs35447019 [P = 3.86 × 10−8], and rs4409676 [P = 4.48 × 10−8]) were common (MAF > 0.26). B and C, Regional linkage disequilibrium (LD) plots of the 2 regions significantly associated with ALS survival. At the 1p36 locus, 4 SNPs passed the genome-wide significant threshold, followed by 87 tagged proxies suggestively associated (P < 10−4). All the associated SNPs mapped within introns 3 to 4 of the CAMTA1 gene. At the 10q23 locus, the top-ranked SNP, rs139550538, intronic to the IDE gene, was in weak (r2 < 0.4) LD with the tagged proxies that were located in the neighbor gene, KIF11.

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Figure 2.
Survival Distribution Across the Genotypes of the Top-Ranked Single-Nucleotide Polymorphisms (SNPs)

Kaplan-Meier curves plot survival distribution. A, IDE rs139550538 distribution of genotypes under a dominant model. Survival in the 226 AA/AT carriers was compared with that in 4030 TT carriers, showing that the presence of at least 1 A allele is associated with a median survival of 30.7 months compared with 36.7 months in TT homozygotes. B, Variant CAMTA1 rs2412208 genotypes under an additive genetic model show 265 GG and 1644 GT carriers with a median survival of 36.0 and 36.8 months, respectively, compared with 40.8 months in 2347 TT carriers. C, Variant CAMTA1 rs2412208 genotypes under a dominant model show survival in 1909 GG/GT and 2347 TT carriers; TT homozygotes have a life span extended by more than 4 months. Kaplan-Meier curves report patients’ survival up to 10 years, plotted in SPSS software.

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Figure 3.
Forest Plot of CAMTA1 rs2412208 Hazard Ratio (HR) Estimates

Hazard ratio estimates are measured under an additive genetic model across the 7 genome-wide association study (GWAS) data sets (described in detail in eTable 1 in the Supplement). The HR in each cohort was estimated in a multivariate log-additive genetic model using the pacoxph program adjusted by age at onset, sex, and population stratification, whereas the summary HR was calculated by fixed-effects meta-analysis using R library rmeta. Genotype raw data included in each study and combined in the meta-analysis were collected by the Medical Center Utrecht, Utrecht, the Netherlands (UMC-1 and -2), the Beaumont Hospital Dublin, Ireland (Ireland), Massachusetts General Hospital, Boston (MGH), the National Institutes of Health, Bethesda, Maryland (NIH-IT), the Italian Consortium for the Genetics of ALS (SLAGEN), and the UK National MND DNA and Biobank Study (UK). Dark blue boxes indicate single studies and are proportional to the sample sizes; bars indicate 95% CI. Evry indicates University of Evry and Paris, Evry, France, and Hospital de la Salpetriere, Paris, France; KCL, King’s College London.

aIncludes samples from Umeå and Leuven.

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