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.
Dunckley
Travis
T
Translational Genomics Research Inst., Phoenix, AZ 85004, USA.
Huentelman
Matthew J
MJ
Craig
David W
DW
Pearson
John V
JV
Szelinger
Szabolcs
S
Joshipura
Keta
K
Halperin
Rebecca F
RF
Stamper
Chelsea
C
Jensen
Kendall R
KR
Letizia
David
D
Hesterlee
Sharon E
SE
Pestronk
Alan
A
Levine
Todd
T
Bertorini
Tulio
T
Graves
Michael C
MC
Mozaffar
Tahseen
T
Jackson
Carlayne E
CE
Bosch
Peter
P
McVey
April
A
Dick
Arthur
A
Barohn
Richard
R
Lomen-Hoerth
Catherine
C
Rosenfeld
Jeffrey
J
O'connor
Daniel T
DT
Zhang
Kuixing
K
Crook
Richard
R
Ryberg
Henrik
H
Hutton
Michael
M
Katz
Jonathan
J
Simpson
Ericka P
EP
Mitsumoto
Hiroshi
H
Bowser
Robert
R
Miller
Robert G
RG
Appel
Stanley H
SH
Stephan
Dietrich A
DA
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