Whole-genome analysis of sporadic amyotrophic lateral sclerosis
Document Type
Article
Abstract
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 = 3.0 x 10-4; 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. Copyright © 2007 Massachusetts Medical Society.
Publication Date
8-23-2007
Publication Title
New England Journal of Medicine
ISSN
00284793
E-ISSN
15334406
Volume
357
Issue
8
First Page
775
Last Page
788
PubMed ID
17671248
Digital Object Identifier (DOI)
10.1056/NEJMoa070174
Recommended Citation
Dunckley, Travis; Huentelman, Matthew J.; Craig, David W.; Pearson, John V.; Szelinger, Szabolcs; Joshipura, Keta; Halperin, Rebecca F.; Stamper, Chelsea; Jensen, Kendall R.; Letizia, David; Hesterlee, Sharon E.; Pestronk, Alan; Levine, Todd; Bertorini, Tulio; Graves, Michael C.; Mozaffar, Tahseen; Jackson, Carlayne E.; Bosch, Peter; McVey, April; Dick, Arthur; Barohn, Richard; Lomen-Hoerth, Catherine; Rosenfeld, Jeffrey; O'Connor, Daniel T.; Zhang, Kuixing; Crook, Richard; Ryberg, Henrik; Hutton, Michael; Katz, Jonathan; Simpson, Ericka P.; Mitsumoto, Hiroshi; and Bowser, Robert, "Whole-genome analysis of sporadic amyotrophic lateral sclerosis" (2007). Translational Neuroscience. 1063.
https://scholar.barrowneuro.org/neurobiology/1063