TY - JOUR
T1 - Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis
AU - Fogh, Isabella
AU - Lin, Kuang
AU - Tiloca, Cinzia
AU - Rooney, James
AU - Gellera, Cinzia
AU - Diekstra, Frank P.
AU - Ratti, Antonia
AU - Shatunov, Aleksey
AU - Van Es, Michael A.
AU - Proitsi, Petra
AU - Jones, Ashley
AU - Sproviero, William
AU - Chiò, Adriano
AU - McLaughlin, Russell Lewis
AU - Sorarù, Gianni
AU - Corrado, Lucia
AU - Stahl, Daniel
AU - Del Bo, Roberto
AU - Cereda, Cristina
AU - Castellotti, Barbara
AU - Glass, Jonathan D.
AU - Newhouse, Steven
AU - Dobson, Richard
AU - Smith, Bradley N.
AU - Topp, Simon
AU - Van Rheenen, Wouter
AU - Meininger, Vincent
AU - Melki, Judith
AU - Morrison, Karen E.
AU - Shaw, Pamela J.
AU - Leigh, P. Nigel
AU - Andersen, Peter M.
AU - Comi, Giacomo P.
AU - Ticozzi, Nicola
AU - Mazzini, Letizia
AU - D'Alfonso, Sandra
AU - Traynor, Bryan J.
AU - Van Damme, Philip
AU - Robberecht, Wim
AU - Brown, Robert H.
AU - Landers, John E.
AU - Hardiman, Orla
AU - Lewis, Cathryn M.
AU - Van Den Berg, Leonard H.
AU - Shaw, Christopher E.
AU - Veldink, Jan H.
AU - Silani, Vincenzo
AU - Al-Chalabi, Ammar
AU - Powell, John
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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 bymeta-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.
AB - 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 bymeta-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.
UR - http://www.scopus.com/inward/record.url?scp=84978101069&partnerID=8YFLogxK
U2 - 10.1001/jamaneurol.2016.1114
DO - 10.1001/jamaneurol.2016.1114
M3 - Article
C2 - 27244217
SN - 2168-6149
VL - 73
SP - 812
EP - 820
JO - JAMA Neurology
JF - JAMA Neurology
IS - 7
ER -