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

Publication ,  Journal Article
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 ...
Published in: Hum Mol Genet
April 15, 2009

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.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

April 15, 2009

Volume

18

Issue

8

Start / End Page

1524 / 1532

Location

England

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Genome-Wide Association Study
  • Genome, Human
  • Genetics & Heredity
  • Case-Control Studies
  • Amyotrophic Lateral Sclerosis
  • 3105 Genetics
  • 11 Medical and Health Sciences
  • 06 Biological Sciences
 

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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. Hum Mol Genet, 18(8), 1524–1532. https://doi.org/10.1093/hmg/ddp059
Chiò, Adriano, Jennifer C. Schymick, Gabriella Restagno, Sonja W. Scholz, Federica Lombardo, Shiao-Lin Lai, Gabriele Mora, et al. “A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.Hum Mol Genet 18, no. 8 (April 15, 2009): 1524–32. https://doi.org/10.1093/hmg/ddp059.
Chiò A, Schymick JC, Restagno G, Scholz SW, Lombardo F, Lai S-L, et al. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2009 Apr 15;18(8):1524–32.
Chiò, Adriano, et al. “A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.Hum Mol Genet, vol. 18, no. 8, Apr. 2009, pp. 1524–32. Pubmed, doi:10.1093/hmg/ddp059.
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. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2009 Apr 15;18(8):1524–1532.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

April 15, 2009

Volume

18

Issue

8

Start / End Page

1524 / 1532

Location

England

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Genome-Wide Association Study
  • Genome, Human
  • Genetics & Heredity
  • Case-Control Studies
  • Amyotrophic Lateral Sclerosis
  • 3105 Genetics
  • 11 Medical and Health Sciences
  • 06 Biological Sciences