A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.
Chiò
Adriano
A
Department of Neuroscience, University of Turin, Turin, Italy.
Schymick
Jennifer C
JC
Restagno
Gabriella
G
Scholz
Sonja W
SW
Lombardo
Federica
F
Lai
Shiao-Lin
SL
Mora
Gabriele
G
Fung
Hon-Chung
HC
Britton
Angela
A
Arepalli
Sampath
S
Gibbs
J Raphael
JR
Nalls
Michael
M
Berger
Stephen
S
Kwee
Lydia Coulter
LC
Oddone
Eugene Z
EZ
Ding
Jinhui
J
Crews
Cynthia
C
Rafferty
Ian
I
Washecka
Nicole
N
Hernandez
Dena
D
Ferrucci
Luigi
L
Bandinelli
Stefania
S
Guralnik
Jack
J
Macciardi
Fabio
F
Torri
Federica
F
Lupoli
Sara
S
Chanock
Stephen J
SJ
Thomas
Gilles
G
Hunter
David J
DJ
Gieger
Christian
C
Wichmann
H Erich
HE
Calvo
Andrea
A
Mutani
Roberto
R
Battistini
Stefania
S
Giannini
Fabio
F
Caponnetto
Claudia
C
Mancardi
Giovanni Luigi
GL
La Bella
Vincenzo
V
Valentino
Francesca
F
Monsurrò
Maria Rosaria
MR
Tedeschi
Gioacchino
G
Marinou
Kalliopi
K
Sabatelli
Mario
M
Conte
Amelia
A
Mandrioli
Jessica
J
Sola
Patrizia
P
Salvi
Fabrizio
F
Bartolomei
Ilaria
I
Siciliano
Gabriele
G
Carlesi
Cecilia
C
Orrell
Richard W
RW
Talbot
Kevin
K
Simmons
Zachary
Z
Connor
James
J
Pioro
Erik P
EP
Dunkley
Travis
T
Stephan
Dietrich A
DA
Kasperaviciute
Dalia
D
Fisher
Elizabeth M
EM
Jabonka
Sibylle
S
Sendtner
Michael
M
Beck
Marcus
M
Bruijn
Lucie
L
Rothstein
Jeffrey
J
Schmidt
Silke
S
Singleton
Andrew
A
Hardy
John
J
Traynor
Bryan J
BJ
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide