A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis

Adriano Chiò, Jennifer C. Schymick, Gabriella Restagno, Sonja W. Scholz, Federica Lombardo, Shiao Lin Lai, Gabriele Mora, Hon Chung Fung, Angela Britton, Sampath Arepalli, J. Raphael Gibbs, Michael Nalls, Stephen Berger, Lydia Coulter Kwee, Eugene Z. Oddone, Jinhui Ding, Cynthia Crews, Ian Rafferty, Nicole Washecka, Dena HernandezLuigi Ferrucci, Stefania Bandinelli, Jack Guralnik, Fabio Macciardi, Federica Torri, Sara Lupoli, Stephen J. Chanock, Gilles Thomas, David J. Hunter, Christian Gieger, H. Erich Wichmann, Andrea Calvo, Roberto Mutani, Stefania Battistini, Fabio Giannini, Claudia Caponnetto, Giovanni Luigi Mancardi, Vincenzo La Bella, Francesca Valentino, Maria Rosaria Monsurrò, Gioacchino Tedeschi, Kalliopi Marinou, Mario Sabatelli, Amelia Conte, Jessica Mandrioli, Patrizia Sola, Fabrizio Salvi, Ilaria Bartolomei, Gabriele Siciliano, Cecilia Carlesi, Richard W. Orrell, Kevin Talbot, Zachary Simmons, James Connor, Erik P. Pioro, Travis Dunkley, Dietrich A. Stephan, Dalia Kasperaviciute, Elizabeth M. Fisher, Sibylle Jabonka, Michael Sendtner, Marcus Beck, Lucie Bruijn, Jeffrey Rothstein, Silke Schmidt, Andrew Singleton, John Hardy, Bryan J. Traynor

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 × 10-7 and 1.16 × 10-6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.

Original languageEnglish (US)
Pages (from-to)1524-1532
Number of pages9
JournalHuman Molecular Genetics
Volume18
Issue number8
DOIs
StatePublished - Apr 20 2009

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Genome-Wide Association Study
Amyotrophic Lateral Sclerosis
Single Nucleotide Polymorphism
Odds Ratio
Nerve Degeneration
Linkage Disequilibrium
Motor Neurons
Chromosomes
Genotype
Genome
Amyotrophic lateral sclerosis 1
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Chiò, A., Schymick, J. C., Restagno, G., Scholz, S. W., Lombardo, F., Lai, S. L., ... Traynor, B. J. (2009). A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Human Molecular Genetics, 18(8), 1524-1532. https://doi.org/10.1093/hmg/ddp059
Chiò, Adriano ; Schymick, Jennifer C. ; Restagno, Gabriella ; Scholz, Sonja W. ; Lombardo, Federica ; Lai, Shiao Lin ; Mora, Gabriele ; Fung, Hon Chung ; Britton, Angela ; Arepalli, Sampath ; Gibbs, J. Raphael ; Nalls, Michael ; Berger, Stephen ; Kwee, Lydia Coulter ; Oddone, Eugene Z. ; Ding, Jinhui ; Crews, Cynthia ; Rafferty, Ian ; Washecka, Nicole ; Hernandez, Dena ; Ferrucci, Luigi ; Bandinelli, Stefania ; Guralnik, Jack ; Macciardi, Fabio ; Torri, Federica ; Lupoli, Sara ; Chanock, Stephen J. ; Thomas, Gilles ; Hunter, David J. ; Gieger, Christian ; Wichmann, H. Erich ; Calvo, Andrea ; Mutani, Roberto ; Battistini, Stefania ; Giannini, Fabio ; Caponnetto, Claudia ; Mancardi, Giovanni Luigi ; La Bella, Vincenzo ; Valentino, Francesca ; Monsurrò, Maria Rosaria ; Tedeschi, Gioacchino ; Marinou, Kalliopi ; Sabatelli, Mario ; Conte, Amelia ; Mandrioli, Jessica ; Sola, Patrizia ; Salvi, Fabrizio ; Bartolomei, Ilaria ; Siciliano, Gabriele ; Carlesi, Cecilia ; Orrell, Richard W. ; Talbot, Kevin ; Simmons, Zachary ; Connor, James ; Pioro, Erik P. ; Dunkley, Travis ; Stephan, Dietrich A. ; Kasperaviciute, Dalia ; Fisher, Elizabeth M. ; Jabonka, Sibylle ; Sendtner, Michael ; Beck, Marcus ; Bruijn, Lucie ; Rothstein, Jeffrey ; Schmidt, Silke ; Singleton, Andrew ; Hardy, John ; Traynor, Bryan J. / A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 8. pp. 1524-1532.
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abstract = "The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 × 10-7 and 1.16 × 10-6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.",
author = "Adriano Chi{\`o} and Schymick, {Jennifer C.} and Gabriella Restagno and Scholz, {Sonja W.} and Federica Lombardo and Lai, {Shiao Lin} and Gabriele Mora and Fung, {Hon Chung} and Angela Britton and Sampath Arepalli and Gibbs, {J. Raphael} and Michael Nalls and Stephen Berger and Kwee, {Lydia Coulter} and Oddone, {Eugene Z.} and Jinhui Ding and Cynthia Crews and Ian Rafferty and Nicole Washecka and Dena Hernandez and Luigi Ferrucci and Stefania Bandinelli and Jack Guralnik and Fabio Macciardi and Federica Torri and Sara Lupoli and Chanock, {Stephen J.} and Gilles Thomas and Hunter, {David J.} and Christian Gieger and Wichmann, {H. Erich} and Andrea Calvo and Roberto Mutani and Stefania Battistini and Fabio Giannini and Claudia Caponnetto and Mancardi, {Giovanni Luigi} and {La Bella}, Vincenzo and Francesca Valentino and Monsurr{\`o}, {Maria Rosaria} and Gioacchino Tedeschi and Kalliopi Marinou and Mario Sabatelli and Amelia Conte and Jessica Mandrioli and Patrizia Sola and Fabrizio Salvi and Ilaria Bartolomei and Gabriele Siciliano and Cecilia Carlesi and Orrell, {Richard W.} and Kevin Talbot and Zachary Simmons and James Connor and Pioro, {Erik P.} and Travis Dunkley and Stephan, {Dietrich A.} and Dalia Kasperaviciute and Fisher, {Elizabeth M.} and Sibylle Jabonka and Michael Sendtner and Marcus Beck and Lucie Bruijn and Jeffrey Rothstein and Silke Schmidt and Andrew Singleton and John Hardy and Traynor, {Bryan J.}",
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Chiò, A, Schymick, JC, Restagno, G, Scholz, SW, Lombardo, F, Lai, SL, Mora, G, Fung, HC, Britton, A, Arepalli, S, Gibbs, JR, Nalls, M, Berger, S, Kwee, LC, Oddone, EZ, Ding, J, Crews, C, Rafferty, I, Washecka, N, Hernandez, D, Ferrucci, L, Bandinelli, S, Guralnik, J, Macciardi, F, Torri, F, Lupoli, S, Chanock, SJ, Thomas, G, Hunter, DJ, Gieger, C, Wichmann, HE, Calvo, A, Mutani, R, Battistini, S, Giannini, F, Caponnetto, C, Mancardi, GL, La Bella, V, Valentino, F, Monsurrò, MR, Tedeschi, G, Marinou, K, Sabatelli, M, Conte, A, Mandrioli, J, Sola, P, Salvi, F, Bartolomei, I, Siciliano, G, Carlesi, C, Orrell, RW, Talbot, K, Simmons, Z, Connor, J, Pioro, EP, Dunkley, T, Stephan, DA, Kasperaviciute, D, Fisher, EM, Jabonka, S, Sendtner, M, Beck, M, Bruijn, L, Rothstein, J, Schmidt, S, Singleton, A, Hardy, J & Traynor, BJ 2009, 'A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis', Human Molecular Genetics, vol. 18, no. 8, pp. 1524-1532. https://doi.org/10.1093/hmg/ddp059

A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. / Chiò, Adriano; Schymick, Jennifer C.; Restagno, Gabriella; Scholz, Sonja W.; Lombardo, Federica; Lai, Shiao Lin; Mora, Gabriele; Fung, Hon Chung; Britton, Angela; Arepalli, Sampath; Gibbs, J. Raphael; Nalls, Michael; Berger, Stephen; Kwee, Lydia Coulter; Oddone, Eugene Z.; Ding, Jinhui; Crews, Cynthia; Rafferty, Ian; Washecka, Nicole; Hernandez, Dena; Ferrucci, Luigi; Bandinelli, Stefania; Guralnik, Jack; Macciardi, Fabio; Torri, Federica; Lupoli, Sara; Chanock, Stephen J.; Thomas, Gilles; Hunter, David J.; Gieger, Christian; Wichmann, H. Erich; Calvo, Andrea; Mutani, Roberto; Battistini, Stefania; Giannini, Fabio; Caponnetto, Claudia; Mancardi, Giovanni Luigi; La Bella, Vincenzo; Valentino, Francesca; Monsurrò, Maria Rosaria; Tedeschi, Gioacchino; Marinou, Kalliopi; Sabatelli, Mario; Conte, Amelia; Mandrioli, Jessica; Sola, Patrizia; Salvi, Fabrizio; Bartolomei, Ilaria; Siciliano, Gabriele; Carlesi, Cecilia; Orrell, Richard W.; Talbot, Kevin; Simmons, Zachary; Connor, James; Pioro, Erik P.; Dunkley, Travis; Stephan, Dietrich A.; Kasperaviciute, Dalia; Fisher, Elizabeth M.; Jabonka, Sibylle; Sendtner, Michael; Beck, Marcus; Bruijn, Lucie; Rothstein, Jeffrey; Schmidt, Silke; Singleton, Andrew; Hardy, John; Traynor, Bryan J.

In: Human Molecular Genetics, Vol. 18, No. 8, 20.04.2009, p. 1524-1532.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis

AU - Chiò, Adriano

AU - Schymick, Jennifer C.

AU - Restagno, Gabriella

AU - Scholz, Sonja W.

AU - Lombardo, Federica

AU - Lai, Shiao Lin

AU - Mora, Gabriele

AU - Fung, Hon Chung

AU - Britton, Angela

AU - Arepalli, Sampath

AU - Gibbs, J. Raphael

AU - Nalls, Michael

AU - Berger, Stephen

AU - Kwee, Lydia Coulter

AU - Oddone, Eugene Z.

AU - Ding, Jinhui

AU - Crews, Cynthia

AU - Rafferty, Ian

AU - Washecka, Nicole

AU - Hernandez, Dena

AU - Ferrucci, Luigi

AU - Bandinelli, Stefania

AU - Guralnik, Jack

AU - Macciardi, Fabio

AU - Torri, Federica

AU - Lupoli, Sara

AU - Chanock, Stephen J.

AU - Thomas, Gilles

AU - Hunter, David J.

AU - Gieger, Christian

AU - Wichmann, H. Erich

AU - Calvo, Andrea

AU - Mutani, Roberto

AU - Battistini, Stefania

AU - Giannini, Fabio

AU - Caponnetto, Claudia

AU - Mancardi, Giovanni Luigi

AU - La Bella, Vincenzo

AU - Valentino, Francesca

AU - Monsurrò, Maria Rosaria

AU - Tedeschi, Gioacchino

AU - Marinou, Kalliopi

AU - Sabatelli, Mario

AU - Conte, Amelia

AU - Mandrioli, Jessica

AU - Sola, Patrizia

AU - Salvi, Fabrizio

AU - Bartolomei, Ilaria

AU - Siciliano, Gabriele

AU - Carlesi, Cecilia

AU - Orrell, Richard W.

AU - Talbot, Kevin

AU - Simmons, Zachary

AU - Connor, James

AU - Pioro, Erik P.

AU - Dunkley, Travis

AU - Stephan, Dietrich A.

AU - Kasperaviciute, Dalia

AU - Fisher, Elizabeth M.

AU - Jabonka, Sibylle

AU - Sendtner, Michael

AU - Beck, Marcus

AU - Bruijn, Lucie

AU - Rothstein, Jeffrey

AU - Schmidt, Silke

AU - Singleton, Andrew

AU - Hardy, John

AU - Traynor, Bryan J.

PY - 2009/4/20

Y1 - 2009/4/20

N2 - The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 × 10-7 and 1.16 × 10-6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.

AB - The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 × 10-7 and 1.16 × 10-6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.

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Chiò A, Schymick JC, Restagno G, Scholz SW, Lombardo F, Lai SL et al. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Human Molecular Genetics. 2009 Apr 20;18(8):1524-1532. https://doi.org/10.1093/hmg/ddp059