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

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
Pages (from-to)1524-1532
Number of pages9
JournalHuman Molecular Genetics
Volume18
Issue number8
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Chiò, A., Schymick, J. C., Restagno, G., Scholz, S. W., Lombardo, F., Lai, S. L., Mora, G., Fung, H. C., Britton, A., Arepalli, S., Gibbs, J. R., Nalls, M., Berger, S., Kwee, L. C., Oddone, E. Z., Ding, J., Crews, C., Rafferty, I., Washecka, N., ... 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