title: ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS.
  
  
  METHODS
  We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study.
  
  
  RESULTS
  A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016).
  
  
  CONCLUSIONS
  Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.
authors.affiliation: Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
authors.forename: Paul W
authors.initials: PW
authors.lastname: Van Vught
authors.forename: Hylke M
authors.initials: HM
authors.lastname: Blauw
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Christiaan G
authors.initials: CG
authors.lastname: Saris
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Sonja W
authors.initials: SW
authors.lastname: de Jong
authors.forename: Ruben
authors.initials: R
authors.lastname: van 't Slot
authors.forename: Anna
authors.initials: A
authors.lastname: Birve
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.forename: Vianney
authors.initials: V
authors.lastname: de Jong
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Helenius J
authors.initials: HJ
authors.lastname: Schelhaas
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: John H J
authors.initials: JH
authors.lastname: Wokke
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide