Whole-genome analysis of sporadic amyotrophic lateral sclerosis.
BACKGROUND
Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes.


METHODS
We performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls.


RESULTS
We identified 10 genetic loci that are significantly associated (P<0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compared with controls was found for a SNP near an uncharacterized gene known as FLJ10986 (P=3.0x10(-4); odds ratio for having the genotype in patients vs. controls, 1.35; 95% confidence interval, 1.13 to 1.62). The FLJ10986 protein was found to be expressed in the spinal cord and cerebrospinal fluid of patients and of controls. Specific SNPs seem to be associated with sex, age at onset, and site of onset of sporadic ALS.


CONCLUSIONS
Variants of FLJ10986 may confer susceptibility to sporadic ALS. FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease.
Translational Genomics Research Inst., Phoenix, AZ 85004, USA.
Travis
T
Dunckley
Matthew J
MJ
Huentelman
David W
DW
Craig
John V
JV
Pearson
Szabolcs
S
Szelinger
Keta
K
Joshipura
Rebecca F
RF
Halperin
Chelsea
C
Stamper
Kendall R
KR
Jensen
David
D
Letizia
Sharon E
SE
Hesterlee
Alan
A
Pestronk
Todd
T
Levine
Tulio
T
Bertorini
Michael C
MC
Graves
Tahseen
T
Mozaffar
Carlayne E
CE
Jackson
Peter
P
Bosch
April
A
McVey
Arthur
A
Dick
Richard
R
Barohn
Catherine
C
Lomen-Hoerth
Jeffrey
J
Rosenfeld
Daniel T
DT
O'connor
Kuixing
K
Zhang
Richard
R
Crook
Henrik
H
Ryberg
Michael
M
Hutton
Jonathan
J
Katz
Ericka P
EP
Simpson
Hiroshi
H
Mitsumoto
Robert
R
Bowser
Robert G
RG
Miller
Stanley H
SH
Appel
Dietrich A
DA
Stephan
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D002556:Cerebrospinal Fluid Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D008297:Male; D009154:Mutation; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017422:Sequence Analysis, DNA
D002556:Cerebrospinal Fluid Proteins; C522407:FL10986 protein, human