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.
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 ALSpatients 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.
Authors: Hui Wang; Jan H Veldink; Hylke Blauw; Leonard H van den Berg; Roel A Ophoff; Chiara Sabatti Journal: Hum Hered Date: 2009-04-01 Impact factor: 0.444
Authors: Louise V Wain; Inti Pedroso; John E Landers; Gerome Breen; Christopher E Shaw; P Nigel Leigh; Robert H Brown; Martin D Tobin; Ammar Al-Chalabi Journal: PLoS One Date: 2009-12-04 Impact factor: 3.240
Authors: Claire L Simpson; Robin Lemmens; Katarzyna Miskiewicz; Wendy J Broom; Valerie K Hansen; Paul W J van Vught; John E Landers; Peter Sapp; Ludo Van Den Bosch; Joanne Knight; Benjamin M Neale; Martin R Turner; Jan H Veldink; Roel A Ophoff; Vineeta B Tripathi; Ana Beleza; Meera N Shah; Petroula Proitsi; Annelies Van Hoecke; Peter Carmeliet; H Robert Horvitz; P Nigel Leigh; Christopher E Shaw; Leonard H van den Berg; Pak C Sham; John F Powell; Patrik Verstreken; Robert H Brown; Wim Robberecht; Ammar Al-Chalabi Journal: Hum Mol Genet Date: 2008-11-07 Impact factor: 6.150