Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis.
We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.
van Es
Michael A
MA
Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
Veldink
Jan H
JH
Saris
Christiaan G J
CG
Blauw
Hylke M
HM
van Vught
Paul W J
PW
Birve
Anna
A
Lemmens
Robin
R
Schelhaas
Helenius J
HJ
Groen
Ewout J N
EJ
Huisman
Mark H B
MH
van der Kooi
Anneke J
AJ
de Visser
Marianne
M
Dahlberg
Caroline
C
Estrada
Karol
K
Rivadeneira
Fernando
F
Hofman
Albert
A
Zwarts
Machiel J
MJ
van Doormaal
Perry T C
PT
Rujescu
Dan
D
Strengman
Eric
E
Giegling
Ina
I
Muglia
Pierandrea
P
Tomik
Barbara
B
Slowik
Agnieszka
A
Uitterlinden
Andre G
AG
Hendrich
Corinna
C
Waibel
Stefan
S
Meyer
Thomas
T
Ludolph
Albert C
AC
Glass
Jonathan D
JD
Purcell
Shaun
S
Cichon
Sven
S
Nöthen
Markus M
MM
Wichmann
H-Erich
HE
Schreiber
Stefan
S
Vermeulen
Sita H H M
SH
Kiemeney
Lambertus A
LA
Wokke
John H J
JH
Cronin
Simon
S
McLaughlin
Russell L
RL
Hardiman
Orla
O
Fumoto
Katsumi
K
Pasterkamp
R Jeroen
RJ
Meininger
Vincent
V
Melki
Judith
J
Leigh
P Nigel
PN
Shaw
Christopher E
CE
Landers
John E
JE
Al-Chalabi
Ammar
A
Brown
Robert H
RH
Robberecht
Wim
W
Andersen
Peter M
PM
Ophoff
Roel A
RA
van den Berg
Leonard H
LH
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19; D002899:Chromosomes, Human, Pair 9; D004198:Disease Susceptibility; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide