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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Chiò, A; Schymick, JC; Restagno, G; Scholz, SW; Lombardo, F; Lai, S-L; Mora, G; Fung, H-C; 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

Published Date

  • April 2009

Published In

Volume / Issue

  • 18 / 8

Start / End Page

  • 1524 - 1532

PubMed ID

  • 19193627

Pubmed Central ID

  • 19193627

Electronic International Standard Serial Number (EISSN)

  • 1460-2083

International Standard Serial Number (ISSN)

  • 0964-6906

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddp059

Language

  • eng