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

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

Risultato della ricerca: Articlepeer review

87 Citazioni (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 x 10(-7) and 1.16 x 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.
Lingua originaleEnglish
pagine (da-a)1524-1532
Numero di pagine9
RivistaHuman Molecular Genetics
Volume18
Stato di pubblicazionePublished - 2009

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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