Whole-genome analysis of sporadic amyotrophic lateral sclerosis

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

Research output: Contribution to journalArticle

186 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)775-788
Number of pages14
JournalNew England Journal of Medicine
Volume357
Issue number8
DOIs
StatePublished - Aug 23 2007
Externally publishedYes

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Genome
Single Nucleotide Polymorphism
Genetic Loci
Disease Susceptibility
Amyotrophic lateral sclerosis 1
Age of Onset
Genes
Cerebrospinal Fluid
Spinal Cord
Odds Ratio
Genotype
Confidence Intervals
Population
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dunckley, T., Huentelman, M. J., Craig, D. W., Pearson, J. V., Szelinger, S., Joshipura, K., ... Stephan, D. A. (2007). Whole-genome analysis of sporadic amyotrophic lateral sclerosis. New England Journal of Medicine, 357(8), 775-788. https://doi.org/10.1056/NEJMoa070174

Whole-genome analysis of sporadic amyotrophic lateral sclerosis. / 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; Bowser, Robert; Miller, Robert G.; Appel, Stanley H.; Stephan, Dietrich A.

In: New England Journal of Medicine, Vol. 357, No. 8, 23.08.2007, p. 775-788.

Research output: Contribution to journalArticle

Dunckley, T, Huentelman, MJ, Craig, DW, Pearson, JV, Szelinger, S, Joshipura, K, Halperin, RF, Stamper, C, Jensen, KR, Letizia, D, Hesterlee, SE, Pestronk, A, Levine, T, Bertorini, T, Graves, MC, Mozaffar, T, Jackson, CE, Bosch, P, McVey, A, Dick, A, Barohn, R, Lomen-Hoerth, C, Rosenfeld, J, O'Connor, DT, Zhang, K, Crook, R, Ryberg, H, Hutton, M, Katz, J, Simpson, EP, Mitsumoto, H, Bowser, R, Miller, RG, Appel, SH & Stephan, DA 2007, 'Whole-genome analysis of sporadic amyotrophic lateral sclerosis', New England Journal of Medicine, vol. 357, no. 8, pp. 775-788. https://doi.org/10.1056/NEJMoa070174
Dunckley T, Huentelman MJ, Craig DW, Pearson JV, Szelinger S, Joshipura K et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. New England Journal of Medicine. 2007 Aug 23;357(8):775-788. https://doi.org/10.1056/NEJMoa070174
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 ; Bowser, Robert ; Miller, Robert G. ; Appel, Stanley H. ; Stephan, Dietrich A. / Whole-genome analysis of sporadic amyotrophic lateral sclerosis. In: New England Journal of Medicine. 2007 ; Vol. 357, No. 8. pp. 775-788.
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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 = 3.0 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.",
author = "Travis Dunckley and Huentelman, {Matthew J.} and Craig, {David W.} and Pearson, {John V.} and Szabolcs Szelinger and Keta Joshipura and Halperin, {Rebecca F.} and Chelsea Stamper and Jensen, {Kendall R.} and David Letizia and Hesterlee, {Sharon E.} and Alan Pestronk and Todd Levine and Tulio Bertorini and Graves, {Michael C.} and Tahseen Mozaffar and Jackson, {Carlayne E.} and Peter Bosch and April McVey and Arthur Dick and Richard Barohn and Catherine Lomen-Hoerth and Jeffrey Rosenfeld and O'Connor, {Daniel T.} and Kuixing Zhang and Richard Crook and Henrik Ryberg and Michael Hutton and Jonathan Katz and Simpson, {Ericka P.} and Hiroshi Mitsumoto and Robert Bowser and Miller, {Robert G.} and Appel, {Stanley H.} and Stephan, {Dietrich A.}",
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T1 - Whole-genome analysis of sporadic amyotrophic lateral sclerosis

AU - Dunckley, Travis

AU - Huentelman, Matthew J.

AU - Craig, David W.

AU - Pearson, John V.

AU - Szelinger, Szabolcs

AU - Joshipura, Keta

AU - Halperin, Rebecca F.

AU - Stamper, Chelsea

AU - Jensen, Kendall R.

AU - Letizia, David

AU - Hesterlee, Sharon E.

AU - Pestronk, Alan

AU - Levine, Todd

AU - Bertorini, Tulio

AU - Graves, Michael C.

AU - Mozaffar, Tahseen

AU - Jackson, Carlayne E.

AU - Bosch, Peter

AU - McVey, April

AU - Dick, Arthur

AU - Barohn, Richard

AU - Lomen-Hoerth, Catherine

AU - Rosenfeld, Jeffrey

AU - O'Connor, Daniel T.

AU - Zhang, Kuixing

AU - Crook, Richard

AU - Ryberg, Henrik

AU - Hutton, Michael

AU - Katz, Jonathan

AU - Simpson, Ericka P.

AU - Mitsumoto, Hiroshi

AU - Bowser, Robert

AU - Miller, Robert G.

AU - Appel, Stanley H.

AU - Stephan, Dietrich A.

PY - 2007/8/23

Y1 - 2007/8/23

N2 - 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.

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