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Whole-Genome Analysis of Sporadic Amyotrophic Lateral Sclerosis

Travis Dunckley, Ph.D., Matthew J. Huentelman, Ph.D., David W. Craig, Ph.D., John V. Pearson, B.Sc., Szabolcs Szelinger, B.S., Keta Joshipura, B.S., Rebecca F. Halperin, B.Sc., Chelsea Stamper, B.S., Kendall R. Jensen, Ph.D., David Letizia, M.S., Sharon E. Hesterlee, Ph.D., Alan Pestronk, M.D., Todd Levine, M.D., Tulio Bertorini, M.D., Michael C. Graves, M.D., Tahseen Mozaffar, M.D., Carlayne E. Jackson, M.D., Peter Bosch, M.D., April McVey, M.D., Arthur ****, M.D., Richard Barohn, M.D., Catherine Lomen-Hoerth, M.D., Jeffrey Rosenfeld, M.D., Daniel T. O'Connor, M.D., Kuixing Zhang, M.D., Ph.D., Richard Crook, Ph.D., Henrik Ryberg, Ph.D., Michael Hutton, Ph.D., Jonathan Katz, M.D., Ericka P. Simpson, M.D., Hiroshi Mitsumoto, M.D., Robert Bowser, Ph.D., Robert G. Miller, M.D., Stanley H. Appel, M.D., and Dietrich A. Stephan, Ph.D.




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by Orrell, R. W.







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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=3.0x10–4; 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.



Source Information

From the Translational Genomics Research Inst., Phoenix, AZ (T.D., M.J.H., D.W.C., J.V.P., S.S., K.J., R.F.H., C.S., K.R.J., D.L., D.A.S.); Muscular Dystrophy Association, Tucson, AZ (S.E.H.); Washington Univ. School of Medicine, St. Louis (A.P.); Phoenix Neurological Associates, Phoenix, AZ (T.L.); Univ. of Tennessee, Memphis (T.B.); Univ. of California, Los Angeles (M.C.G.); Univ. of California, Irvine (T.M.); Univ. of Texas Health Science Center, San Antonio (C.E.J.); Mayo Clinic, Scottsdale, AZ (P.B.); Univ. of Kansas Medical Center, Kansas City (A.M., A.D., R.B.); Univ. of California, San Francisco (C.L.-H.); Carolinas Medical Center, Charlotte, NC (J.R.); Univ. of California at San Diego School of Medicine, La Jolla (D.T.O., K.Z.); Mayo Clinic College of Medicine, Jacksonville, FL (R.C., M.H.); Univ. of Pittsburgh Medical Center, Pittsburgh (H.R., R.B.); California Pacific Medical Center, San Francisco (J.K., R.G.M.); Methodist Neurological Inst., Houston (E.P.S., S.H.A.); and Columbia Univ. Medical Center, New York (H.M.).

This article (10.1056/NEJMoa070174) was published at www.nejm.org on August 1, 2007.

Address reprint requests to Dr. Stephan at the Translational Genomics Research Inst., 445 N. Fifth St., Phoenix, AZ 85004, or at dstephan@tgen.org.



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Orrell, R. W. (2007). Understanding the Causes of Amyotrophic Lateral Sclerosis. NEJM 357: 822-823 [Full Text]

http://content.nejm.org/cgi/content/short/357/8/775