The cause of sporadic 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: we followed our initial genome-wide association study of 545,066 SNPs in 553 individuals with ALS and 2,338 controls by testing the 7,600 most associated SNPs from the first stage in three independent cohorts consisting of 2,160 cases and 3,008 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 = 1.17 and 1.18, and P-value = 6.98x10-7 and 1.16x10-6), were located on chromosome 7p13.3 within a 175kb 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 (odds ratio = 1.18 and 1.19, P-value = 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 has been made available online to facilitate such future endevours.
A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis / A. Chiò, J.C. Schymick, G. Restagno, S.W. Scholz, F. Lombardo, S.L. Lai, G. Mora, H.C. Fung, A. Britton, S. Arepalli, J.R. Gibbs, M. Nalls, S. Berger, J. Ding, C. Crews, I. Rafferty, N. Washecka, D. Hernandez, L. Ferrucci, S. Bandinelli, J. Guralnik, F. Macciardi, F. Torri, S. Lupoli, S.J. Chanock , G. Thomas, D. Hunter, C. Gieger, H.E. Wichmann, A. Calvo, R. Mutani, S. Battistini, F. Giannini, C. Caponnetto, G.L. Mancardi, V. La Bella, F. Valentino, M.R. Monsurrò, G. Tedeschi, K. Marinou, M. Sabatelli, A. Conte, J. Mandrioli, P. Sola, F. Salvi, I. Bartolomei, G. Siciliano, C. Carlesi, R.W. Orrell, K. Talbot, Z. Simmons, J. Connor, E.P. Pioro, T. Dunkley, D.A. Stephan, D. Kasperaviciute, E.M. Fisher, S. Jabonka, M. Sendtner, M. Beck, L. Bruijn, J. Rothstein, A. Singleton, J. Hardy, B.J. Traynor. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 18:8(2009 Apr 15), pp. 1524-1532.
A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis
F. Macciardi;F. Torri;S. Lupoli;
2009
Abstract
The cause of sporadic 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: we followed our initial genome-wide association study of 545,066 SNPs in 553 individuals with ALS and 2,338 controls by testing the 7,600 most associated SNPs from the first stage in three independent cohorts consisting of 2,160 cases and 3,008 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 = 1.17 and 1.18, and P-value = 6.98x10-7 and 1.16x10-6), were located on chromosome 7p13.3 within a 175kb 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 (odds ratio = 1.18 and 1.19, P-value = 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 has been made available online to facilitate such future endevours.
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