title: Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the selective death of motor neurons in the brain and spinal cord. Genetic risk factors have been implicated in susceptibility to ALS. Like single nucleotide polymorphisms (SNPs), copy-number variants (CNVs) are a source of genetic variation that have important effects on gene expression and disease phenotypes, and our aim was to identify CNVs that predispose to sporadic ALS.
  
  
  METHODS
  We did a genome-wide screen for CNVs by analysis of Illumina 317K SNP arrays for 406 patients with sporadic ALS and 404 controls. We examined CNVs for association with ALS, and used the Kyoto Encyclopedia of Genes and Genomes database and the Gene Ontology database to investigate the functionality of genes that were deleted exclusively in patients with ALS.
  
  
  RESULTS
  We detected 2328 CNVs in 810 individuals. No CNV locus was significantly associated with sporadic ALS. 406 genes were duplicated or deleted exclusively in patients with ALS and have not been reported in previous studies of CNVs. Of the 390 genes heterozygously deleted in patients with sporadic ALS, 155 (40%) deletions were recorded exclusively in patients. By contrast, of the 323 genes heterozygously deleted in control participants, only 51 (16%) were exclusive to the controls (p=2.15 x 10(-12) for difference between groups). Products of the genes deleted specifically in patients with sporadic ALS include proteins involved in oxidative phosphorylation, regulation of the actin cytoskeleton, and interactions between cytokines and their receptors.
  
  
  CONCLUSIONS
  Common CNVs in the regions of the genome represented on the SNP array are unlikely to be associated with sporadic ALS. However, the high number of genes deleted specifically in patients with ALS strongly suggests that multiple rare deletions might have an important role in ALS pathogenesis.
authors.affiliation: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Hylke M
authors.initials: HM
authors.lastname: Blauw
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
authors.forename: Paul W
authors.initials: PW
authors.lastname: van Vught
authors.forename: Christiaan G J
authors.initials: CG
authors.lastname: Saris
authors.forename: Bert
authors.initials: B
authors.lastname: van der Zwaag
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: J Peter H
authors.initials: JP
authors.lastname: Burbach
authors.forename: John H
authors.initials: JH
authors.lastname: Wokke
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D002874:Chromosome Mapping; D005260:Female; D018628:Gene Dosage / Q000502:physiology*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation; D016678:Genome / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis