Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genome-wide significant result (P = 1.84 x 10(-8)) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.
Landers
John E
JE
Cecil B. Day Neuromuscular Research Laboratory, Massachusetts General Hospital-East, Building 114, Navy Yard, Charlestown, MA 02129, USA. john.landers@umassmed.edu
Melki
Judith
J
Meininger
Vincent
V
Glass
Jonathan D
JD
van den Berg
Leonard H
LH
van Es
Michael A
MA
Sapp
Peter C
PC
van Vught
Paul W J
PW
McKenna-Yasek
Diane M
DM
Blauw
Hylke M
HM
Cho
Ting-Jan
TJ
Polak
Meraida
M
Shi
Lijia
L
Wills
Anne-Marie
AM
Broom
Wendy J
WJ
Ticozzi
Nicola
N
Silani
Vincenzo
V
Ozoguz
Aslihan
A
Rodriguez-Leyva
Ildefonso
I
Veldink
Jan H
JH
Ivinson
Adrian J
AJ
Saris
Christiaan G J
CG
Hosler
Betsy A
BA
Barnes-Nessa
Alayna
A
Couture
Nicole
N
Wokke
John H J
JH
Kwiatkowski
Thomas J
TJ
Ophoff
Roel A
RA
Cronin
Simon
S
Hardiman
Orla
O
Diekstra
Frank P
FP
Leigh
P Nigel
PN
Shaw
Christopher E
CE
Simpson
Claire L
CL
Hansen
Valerie K
VK
Powell
John F
JF
Corcia
Philippe
P
Salachas
François
F
Heath
Simon
S
Galan
Pilar
P
Georges
Franck
F
Horvitz
H Robert
HR
Lathrop
Mark
M
Purcell
Shaun
S
Al-Chalabi
Ammar
A
Brown
Robert H
RH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000401:mortality*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C484407:KIFAP3 protein, human