ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study.
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.
van Es
Michael A
MA
Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
Van Vught
Paul W
PW
Blauw
Hylke M
HM
Franke
Lude
L
Saris
Christiaan G
CG
Andersen
Peter M
PM
Van Den Bosch
Ludo
L
de Jong
Sonja W
SW
van 't Slot
Ruben
R
Birve
Anna
A
Lemmens
Robin
R
de Jong
Vianney
V
Baas
Frank
F
Schelhaas
Helenius J
HJ
Sleegers
Kristel
K
Van Broeckhoven
Christine
C
Wokke
John H J
JH
Wijmenga
Cisca
C
Robberecht
Wim
W
Veldink
Jan H
JH
Ophoff
Roel A
RA
van den Berg
Leonard H
LH
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