Association of a locus in the CAMTA1 gene with survival in patients with sporadic Amyotrophic Lateral Sclerosis

Isabella Fogh; Kuang Lin; Cinzia Tiloca; James Rooney; Cinzia Gellera; Frank P. Diekstra; Antonia Ratti; Aleksey Shatunov; Michael A. van Es; Petroula Proitsi; Ashley Jones; William Sproviero; Adriano Chiò; Russell Lewis McLaughlin; Gianni Sorarù; Lucia Corrado; Daniel Stahl; Roberto Del Bo; Cristina Cereda; Barbara Castellotti; Jonathan D. Glass; Steven Newhouse; Richard Dobson; Bradley N. Smith; Simon Topp; Wouter van Rheenen; Vincent Meininger; Judith Melki; Karen E. Morrison; Pamela J. Shaw; P. Nigel Leigh; Peter M. Andersen; Giacomo P. Comi; Nicola Ticozzi; Letizia Mazzini; Sandra D’Alfonso; Bryan J. Traynor; Philip Van Damme; Wim Robberecht; Robert H. Brown; John E. Landers; Orla Hardiman; Cathryn M. Lewis; Leonard H. van den Berg; Christopher E. Shaw; Jan H. Veldink; Vincenzo Silani; Ammar Al-Chalabi; John Powell

doi:10.1001/jamaneurol.2016.1114

Association of a locus in the CAMTA1 gene with survival in patients with sporadic Amyotrophic Lateral Sclerosis

Isabella Fogh, Kuang Lin, Cinzia Tiloca, James Rooney, Cinzia Gellera, Frank P. Diekstra, Antonia Ratti, Aleksey Shatunov, Michael A. van Es, Petroula Proitsi, Ashley Jones, William Sproviero, Adriano Chiò, Russell Lewis McLaughlin, Gianni Sorarù, Lucia Corrado, Daniel Stahl, Roberto Del Bo, Cristina Cereda, Barbara CastellottiJonathan D. Glass, Steven Newhouse, Richard Dobson, Bradley N. Smith, Simon Topp, Wouter van Rheenen, Vincent Meininger, Judith Melki, Karen E. Morrison, Pamela J. Shaw, P. Nigel Leigh, Peter M. Andersen, Giacomo P. Comi, Nicola Ticozzi, Letizia Mazzini, Sandra D’Alfonso, Bryan J. Traynor, Philip Van Damme, Wim Robberecht, Robert H. Brown, John E. Landers, Orla Hardiman, Cathryn M. Lewis, Leonard H. van den Berg, Christopher E. Shaw, Jan H. Veldink, Vincenzo Silani, Ammar Al-Chalabi, John Powell

Research output: Contribution to journal › Article › peer-review

36 Citations (Scopus)

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.

Original language	English
Pages (from-to)	812-820
Number of pages	9
Journal	JAMA neurology
Volume	73
Issue number	7
DOIs	https://doi.org/10.1001/jamaneurol.2016.1114
Publication status	Published - 01 Jul 2016

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Fogh, I., Lin, K., Tiloca, C., Rooney, J., Gellera, C., Diekstra, F. P., Ratti, A., Shatunov, A., van Es, M. A., Proitsi, P., Jones, A., Sproviero, W., Chiò, A., McLaughlin, R. L., Sorarù, G., Corrado, L., Stahl, D., Del Bo, R., Cereda, C., ... Powell, J. (2016). Association of a locus in the CAMTA1 gene with survival in patients with sporadic Amyotrophic Lateral Sclerosis. JAMA neurology, 73(7), 812-820. https://doi.org/10.1001/jamaneurol.2016.1114

Fogh, Isabella ; Lin, Kuang ; Tiloca, Cinzia ; Rooney, James ; Gellera, Cinzia ; Diekstra, Frank P. ; Ratti, Antonia ; Shatunov, Aleksey ; van Es, Michael A. ; Proitsi, Petroula ; Jones, Ashley ; Sproviero, William ; Chiò, Adriano ; McLaughlin, Russell Lewis ; Sorarù, Gianni ; Corrado, Lucia ; Stahl, Daniel ; Del Bo, Roberto ; Cereda, Cristina ; Castellotti, Barbara ; Glass, Jonathan D. ; Newhouse, Steven ; Dobson, Richard ; Smith, Bradley N. ; Topp, Simon ; van Rheenen, Wouter ; Meininger, Vincent ; Melki, Judith ; Morrison, Karen E. ; Shaw, Pamela J. ; Leigh, P. Nigel ; Andersen, Peter M. ; Comi, Giacomo P. ; Ticozzi, Nicola ; Mazzini, Letizia ; D’Alfonso, Sandra ; Traynor, Bryan J. ; Van Damme, Philip ; Robberecht, Wim ; Brown, Robert H. ; Landers, John E. ; Hardiman, Orla ; Lewis, Cathryn M. ; van den Berg, Leonard H. ; Shaw, Christopher E. ; Veldink, Jan H. ; Silani, Vincenzo ; Al-Chalabi, Ammar ; Powell, John. / Association of a locus in the CAMTA1 gene with survival in patients with sporadic Amyotrophic Lateral Sclerosis. In: JAMA neurology. 2016 ; Vol. 73, No. 7. pp. 812-820.

@article{0b803266b8cb445eb51064a3633aa438,

title = "Association of a locus in the CAMTA1 gene with survival in patients with sporadic Amyotrophic Lateral Sclerosis",

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.",

author = "Isabella Fogh and Kuang Lin and Cinzia Tiloca and James Rooney and Cinzia Gellera and Diekstra, {Frank P.} and Antonia Ratti and Aleksey Shatunov and {van Es}, {Michael A.} and Petroula Proitsi and Ashley Jones and William Sproviero and Adriano Chi{\`o} and McLaughlin, {Russell Lewis} and Gianni Sorar{\`u} and Lucia Corrado and Daniel Stahl and {Del Bo}, Roberto and Cristina Cereda and Barbara Castellotti and Glass, {Jonathan D.} and Steven Newhouse and Richard Dobson and Smith, {Bradley N.} and Simon Topp and {van Rheenen}, Wouter and Vincent Meininger and Judith Melki and Morrison, {Karen E.} and Shaw, {Pamela J.} and Leigh, {P. Nigel} and Andersen, {Peter M.} and Comi, {Giacomo P.} and Nicola Ticozzi and Letizia Mazzini and Sandra D{\textquoteright}Alfonso and Traynor, {Bryan J.} and {Van Damme}, Philip and Wim Robberecht and Brown, {Robert H.} and Landers, {John E.} and Orla Hardiman and Lewis, {Cathryn M.} and {van den Berg}, {Leonard H.} and Shaw, {Christopher E.} and Veldink, {Jan H.} and Vincenzo Silani and Ammar Al-Chalabi and John Powell",

year = "2016",

month = jul,

day = "1",

doi = "10.1001/jamaneurol.2016.1114",

language = "English",

volume = "73",

pages = "812--820",

journal = "JAMA neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "7",

}

Fogh, I, Lin, K, Tiloca, C, Rooney, J, Gellera, C, Diekstra, FP, Ratti, A, Shatunov, A, van Es, MA, Proitsi, P, Jones, A, Sproviero, W, Chiò, A, McLaughlin, RL, Sorarù, G, Corrado, L, Stahl, D, Del Bo, R, Cereda, C, Castellotti, B, Glass, JD, Newhouse, S, Dobson, R, Smith, BN, Topp, S, van Rheenen, W, Meininger, V, Melki, J, Morrison, KE, Shaw, PJ, Leigh, PN, Andersen, PM, Comi, GP, Ticozzi, N, Mazzini, L, D’Alfonso, S, Traynor, BJ, Van Damme, P, Robberecht, W, Brown, RH, Landers, JE, Hardiman, O, Lewis, CM, van den Berg, LH, Shaw, CE, Veldink, JH, Silani, V, Al-Chalabi, A & Powell, J 2016, 'Association of a locus in the CAMTA1 gene with survival in patients with sporadic Amyotrophic Lateral Sclerosis', JAMA neurology, vol. 73, no. 7, pp. 812-820. https://doi.org/10.1001/jamaneurol.2016.1114

Association of a locus in the CAMTA1 gene with survival in patients with sporadic Amyotrophic Lateral Sclerosis. / Fogh, Isabella; Lin, Kuang; Tiloca, Cinzia; Rooney, James; Gellera, Cinzia; Diekstra, Frank P.; Ratti, Antonia; Shatunov, Aleksey; van Es, Michael A.; Proitsi, Petroula; Jones, Ashley; Sproviero, William; Chiò, Adriano; McLaughlin, Russell Lewis; Sorarù, Gianni; Corrado, Lucia; Stahl, Daniel; Del Bo, Roberto; Cereda, Cristina; Castellotti, Barbara; Glass, Jonathan D.; Newhouse, Steven; Dobson, Richard; Smith, Bradley N.; Topp, Simon; van Rheenen, Wouter; Meininger, Vincent; Melki, Judith; Morrison, Karen E.; Shaw, Pamela J.; Leigh, P. Nigel; Andersen, Peter M.; Comi, Giacomo P.; Ticozzi, Nicola; Mazzini, Letizia; D’Alfonso, Sandra; Traynor, Bryan J.; Van Damme, Philip; Robberecht, Wim; Brown, Robert H.; Landers, John E.; Hardiman, Orla; Lewis, Cathryn M.; van den Berg, Leonard H.; Shaw, Christopher E.; Veldink, Jan H.; Silani, Vincenzo; Al-Chalabi, Ammar; Powell, John.

In: JAMA neurology, Vol. 73, No. 7, 01.07.2016, p. 812-820.

Research output: Contribution to journal › Article › peer-review

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, Petroula

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 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.

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 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.

U2 - 10.1001/jamaneurol.2016.1114

DO - 10.1001/jamaneurol.2016.1114

M3 - Article

VL - 73

SP - 812

EP - 820

JO - JAMA neurology

JF - JAMA neurology

SN - 2168-6149

IS - 7

ER -