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. Veldink; Roel A. Ophoff; Leonard H. van den Berg

doi:10.1016/S1474-4422(07)70222-3

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

Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Research output: Contribution to journal › Article › Academic › peer-review

188 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 language	English
Pages (from-to)	869-877
Number of pages	9
Journal	Lancet Neurology
Volume	6
Issue number	10
DOIs	https://doi.org/10.1016/S1474-4422(07)70222-3
Publication status	Published - 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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van Es, M. A., Van Vught, P. W., Blauw, H. M., Franke, L., Saris, C. G., Andersen, P. M., Van Den Bosch, L., de Jong, S. W., van 't Slot, R., Birve, A., Lemmens, R., de Jong, V., Baas, F., Schelhaas, H. J., Sleegers, K., Van Broeckhoven, C., Wokke, J. H. J., Wijmenga, C., Robberecht, W., ... van den Berg, L. H. (2007). ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurology, 6(10), 869-877. https://doi.org/10.1016/S1474-4422(07)70222-3

@article{298019c4f429496095e72dc840dbeead,

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.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.",

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

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

year = "2007",

month = oct,

doi = "10.1016/S1474-4422(07)70222-3",

language = "English",

volume = "6",

pages = "869--877",

journal = "Lancet Neurology",

issn = "1474-4422",

publisher = "ELSEVIER SCIENCE INC",

number = "10",

}

van Es, MA, Van Vught, PW, Blauw, HM, Franke, L, Saris, CG, Andersen, PM, Van Den Bosch, L, de Jong, SW, van 't Slot, R, Birve, A, Lemmens, R, de Jong, V, Baas, F, Schelhaas, HJ, Sleegers, K, Van Broeckhoven, C, Wokke, JHJ, Wijmenga, C, Robberecht, W, Veldink, JH, Ophoff, RA & van den Berg, LH 2007, 'ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study', Lancet Neurology, vol. 6, no. 10, pp. 869-877. https://doi.org/10.1016/S1474-4422(07)70222-3

TY - JOUR

T1 - ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis

T2 - a genome-wide association study

AU - van Es, Michael A.

AU - Van Vught, Paul W.

AU - Blauw, Hylke M.

AU - Franke, Lude

AU - Saris, Christiaan G.

AU - Andersen, Peter M.

AU - Van Den Bosch, Ludo

AU - de Jong, Sonja W.

AU - van 't Slot, Ruben

AU - Birve, Anna

AU - Lemmens, Robin

AU - de Jong, Vianney

AU - Baas, Frank

AU - Schelhaas, Helenius J.

AU - Sleegers, Kristel

AU - Van Broeckhoven, Christine

AU - Wokke, John H. J.

AU - Wijmenga, Cisca

AU - Robberecht, Wim

AU - Veldink, Jan H.

AU - Ophoff, Roel A.

AU - van den Berg, Leonard H.

PY - 2007/10

Y1 - 2007/10

N2 - 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.

AB - 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.

KW - MOTOR-NEURON DISEASE

KW - INOSITOL 1,4,5-TRISPHOSPHATE

KW - DUTCH POPULATION

KW - CALCIUM-RELEASE

KW - ALS

KW - MUTATIONS

KW - APOPTOSIS

KW - BLOOD

KW - POLYMORPHISMS

KW - DEGENERATION

U2 - 10.1016/S1474-4422(07)70222-3

DO - 10.1016/S1474-4422(07)70222-3

M3 - Article

SN - 1474-4422

VL - 6

SP - 869

EP - 877

JO - Lancet Neurology

JF - Lancet Neurology

IS - 10

ER -

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

Abstract

Keywords

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