Whole-genome analysis of sporadic amyotrophic lateral sclerosis


Travis Dunckley, Translational Genomics Research Institute
Matthew J. Huentelman, Translational Genomics Research Institute
David W. Craig, Translational Genomics Research Institute
John V. Pearson, Translational Genomics Research Institute
Szabolcs Szelinger, Translational Genomics Research Institute
Keta Joshipura, Translational Genomics Research Institute
Rebecca F. Halperin, Translational Genomics Research Institute
Chelsea Stamper, Translational Genomics Research Institute
Kendall R. Jensen, Translational Genomics Research Institute
David Letizia, Translational Genomics Research Institute
Sharon E. Hesterlee, Muscular Dystrophy Association
Alan Pestronk, Washington University School of Medicine in St. Louis
Todd Levine, Phoenix Neurological Associates
Tulio Bertorini, University of Tennessee Health Science Center
Michael C. Graves, University of California, Los Angeles
Tahseen Mozaffar, University of California, Irvine
Carlayne E. Jackson, The University of Texas at San Antonio
Peter Bosch, Mayo Clinic Scottsdale-Phoenix, Arizona
April McVey, University of Kansas Medical Center
Arthur Dick, University of Kansas Medical Center
Richard Barohn, University of Kansas Medical Center
Catherine Lomen-Hoerth, University of California, San Francisco
Jeffrey Rosenfeld, Carolinas Medical Center
Daniel T. O'Connor, University of California, San Diego
Kuixing Zhang, University of California, San Diego
Richard Crook, Mayo Clinic in Jacksonville, Florida
Henrik Ryberg, University of Pittsburgh Medical Center
Michael Hutton, Mayo Clinic in Jacksonville, Florida
Jonathan Katz, California Pacific Medical Center
Ericka P. Simpson, Houston Methodist
Hiroshi Mitsumoto, Columbia University Irving Medical Center
Robert Bowser, University of Pittsburgh Medical CenterFollow

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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.

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New England Journal of Medicine









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