Genome-Wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data

Background
The cause of sporadic ALS is currently unknown. Despite evidence for a role for genetics, no common genetic variants have been unequivocally linked to sporadic ALS. We sought to identify genetic variants associated with an increased or decreased risk for developing ALS in a cohort of American sporadic cases.

Methods
We undertook a genome-wide association study using publicly available samples from 276 patients with sporadic ALS and 271 neurologically normal controls. 555 352 unique SNPs were assayed in each sample using the Illumina Infinium II HumanHap550 SNP chip.

Findings
More than 300 million genotypes were produced in 547 participants. These raw genotype data are freely available on the internet and represent the first publicly accessible SNP data for ALS cases. 34 SNPs with a p value less than 0.0001 (two degrees of freedom) were found, although none of these reached significance after Bonferroni correction.

Interpretation
We generated publicly available genotype data for sporadic ALS patients and controls. No single locus was definitively associated with increased risk of developing disease, although potentially associated candidate SNPs were identified.

Reprinted from Lancet Neurology, volume 6, Schymick JC, Scholz SW, Fung HC, et al. Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data, 322-8, 2007, with permission from Elsevier.

This study utilized the NINDS Repository Motor Neuron Disease/ALS Study, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection for a first stage whole genome analysis.

• Study Weblinks:
  • NINDS Amyotrophic Lateral Sclerosis
  • NINDS Repository at Coriell Motor Neuron Diseases Resources
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 544
• Subject Sample Telemetry Report (SSTR)

Cases
Samples were obtained from the NINDS Neurogenetics Repository at the Coriell Institute for Medical Research, NJ, USA. All patients and controls gave written informed consent to participate in the study. DNA from 276 unique and unrelated, white, non-Hispanic individuals diagnosed with sporadic ALS were selected for the analysis. Only patients with probable, clinically probable (laboratory supported or definite ALS), and those without a reported family history of ALS were included in this study. In 43 (16%) of the ALS samples, the depositor stated that mutations in SOD1 were not present. SOD1 status of the remaining 233 patients with ALS was not assessed. The age of patients at onset of the disease ranged from 26 years to 87 years (mean 54.8 years). Disease onset was defined as the time when weakness was first noted. All patients were queried about family history of ALS, other motor neuron diseases, Parkinson's disease, Alzheimer's disease, dementia, and other neurodegenerative diseases.

Controls
The panels that contained samples from neurologically normal controls were NDPT002, NDPT006, and NDPT008; these comprised DNA from 275 unique participants and one replicate sample. These blood samples were drawn from unrelated, white, non-Hispanic individuals at many different sites within the USA (Mid-Atlantic [DE, MD, PA, VA, WV; 22% of control samples]; Southeast [AL, FL, GA; 32%]; Midwest [MN, OH, IL; 31%]; Southwest [AZ; 5%]; and New England [MA, NY, VT; 10%]). Participants underwent a detailed medical history interview. None had a history of ALS, Alzheimer's disease, ataxia, autism, bipolar disorder, brain aneurysm, dementia, dystonia, or Parkinson's disease. Folstein mini-mental state examination scores ranged from 26 to 30. All participants were interviewed for family history in detail. None had any first-degree relative with a known primary neurological disorder, including ALS, ataxia, autism, brain aneurysm, dystonia, Parkinson's disease, and schizophrenia. The control and case cohorts were drawn from the same ethnic origin, but were not matched by age or sex with the ALS samples. The control cohort consisted of 131 men and 144 women and the mean age at sample collection was 68 years (range 55-88).

• Primary Phenotype: Amyotrophic Lateral Sclerosis

• Co-Investigators
  • J.C. Schymick. Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD.
  • S.W. Scholz. Molecular Genetic Unit, NIA, NIH, Bethesda, MD.
  • H.C. Fung. Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD.
  • A. Britton. Molecular Genetic Unit, NIA, NIH, Bethesda, MD.
  • S. Arepalli. Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD.
  • J.R. Gibbs. Computational Biology Core, NIA, NIH, Bethesda, MD.
  • F. Lombardo. Department of Clinical Pathology, ASO OIRM-S Anna, Turin, Italy.
  • M. Matarin. Molecular Genetic Unit, NIA, NIH, Bethesda, MD.
  • D. Kasperaviciute. Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London, UK.
  • D.G. Hernandez. Molecular Genetic Unit, NIA, NIH, Bethesda, MD.
  • C. Crews. Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD.
  • L. Bruijn. ALS Association, Palm Harbor, FL.
  • J. Rothstein. Neurology Department, Johns Hopkins University, Baltimore, MD.
  • G. Mora. Division of Neurorehabilitation, Istituto Scientifico di Pavia, Italy.
  • G. Restagno. Department of Clinical Pathology, ASO OIRM-S Anna, Turin, Italy.
  • A. Chiò. Department of Neuroscience, University of Turin, Turin, Italy.
  • A. Singleton. Molecular Genetic Unit, NIA, NIH, Bethesda, MD.
• Principal Investigators
  • J. Hardy. Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD.
  • B.J. Traynor. SDGE, NIMH, NIH, Bethesda, MD and Neurology Department, Johns Hopkins University, Baltimore, MD.
• NINDS Repository Project Officer
  • K.A. Gwinn. National Institute for Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
• NINDS Repository Principal Investigator
  • R.A. Corriveau. Coriell Institute for Medical Research, Camden, NJ, USA.
• Clinical Investigators, ALSRG
  • H. Mitsumoto. Eleanor and Lou Gehrig MDA/ALS Research Center, Columbia University, New York, NY, USA.
  • R.H. Brown. Massachusetts General Hospital, Charlestown, MA, USA.
  • M. Cudkowicz. Massachusetts General Hospital, Charlestown, MA, USA.
  • P.H. Gordon. Eleanor and Lou Gehrig MDA/ALS Research Center, Columbia University, New York, NY, USA.
  • E.J. Kasarkis. University of Kentucky, Lexington, KY, USA.
  • P. Kaufmann. Eleanor and Lou Gehrig MDA/ALS Research Center, Columbia University, New York, NY, USA.
  • R. Miller. California Pacific Medical Center, San Francisco, CA, USA.
  • E. Sorenson. Mayo Medical Center, Rochester, MN, USA.
  • R. Tandan. University of Vermont, Burlington, VT, USA.
• The ALSRG
  • Various members, Academic Neurologists. See Kaufmann P, Misumoto H (2006) ALS Research Group (ALSRG): Second meeting, a summary report. Amyotrophic Lateral Sclerosis 7: 252-255.