ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study

Michael A. van Es, Paul W. Van Vught, Hylke M. Blauw, Lude Franke, Christiaan G. Saris, Peter M. Andersen, Ludo Van Den Bosch, Sonja W. de Jong, Ruben van 't Slot, Anna Birve, Robin Lemmens, Vianney de Jong, Frank Baas, Helenius J. Schelhaas, Kristel Sleegers, Christine Van Broeckhoven, John H. J. Wokke, Cisca Wijmenga, Wim Robberecht, Jan H. VeldinkRoel A. Ophoff, Leonard H. van den Berg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

170 Citations (Scopus)

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.

Findings 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).

Interpretation 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.

Original languageEnglish
Pages (from-to)869-877
Number of pages9
JournalLancet Neurology
Volume6
Issue number10
DOIs
Publication statusPublished - Oct-2007

Keywords

  • MOTOR-NEURON DISEASE
  • INOSITOL 1,4,5-TRISPHOSPHATE
  • DUTCH POPULATION
  • CALCIUM-RELEASE
  • ALS
  • MUTATIONS
  • APOPTOSIS
  • BLOOD
  • POLYMORPHISMS
  • DEGENERATION

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