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 Dick, 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.
Background Approximately 90% of persons with amyotrophic lateralsclerosis (ALS) have the sporadic form, which may be causedby the interaction of multiple environmental factors and previouslyunknown genes.
Methods We performed a genomewide association analysis using766,955 single-nucleotide polymorphisms (SNPs) found in 386white patients with sporadic ALS and 542 neurologically normalwhite controls (the discovery series). Associations of SNPswith sporadic ALS were confirmed in two independent replicationpopulations: replication series 1, with 766 case patients withthe disease and 750 neurologically normal controls, and replicationseries 2, with 135 case patients and 275 controls.
Results We identified 10 genetic loci that are significantlyassociated (P<0.05) with sporadic ALS in three independentseries of case patients and controls and an additional 41 locithat had significant associations in two of the three series.The most significant association with disease in white casepatients as compared with controls was found for a SNP nearan 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 proteinwas found to be expressed in the spinal cord and cerebrospinalfluid of patients and of controls. Specific SNPs seem to beassociated with sex, age at onset, and site of onset of sporadicALS.
Conclusions Variants of FLJ10986 may confer susceptibility tosporadic ALS. FLJ10986 and 50 other candidate loci warrant furtherinvestigation for their potential role in conferring susceptibilityto 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{at}tgen.org.
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