Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis

John E. Landers, Judith Melki, Vincent Meininger, Jonathan D. Glass, Leonard H. Van Den Berg, Michael A. Van Es, Peter C. Sapp, Paul W J Van Vught, Diane M. McKenna-Yasek, Hylke M. Blauw, Ting Jan Cho, Meraida Polak, Lijia Shi, Anne Marie Wills, Wendy J. Broom, Nicola Ticozzi, Vincenzo Silani, Aslihan Ozoguz, Ildefonso Rodriguez-Leyva, Jan H. VeldinkAdrian J. Ivinson, Christiaan G J Saris, Betsy A. Hosler, Alayna Barnes-Nessa, Nicole Couture, John H J Wokke, Thomas J. Kwiatkowski, Roel A. Ophoff, Simon Cronin, Orla Hardiman, Frank P. Diekstra, P. Nigel Leigh, Christopher E. Shaw, Claire L. Simpson, Valerie K. Hansen, John F. Powell, Philippe Corcia, François Salachas, Simon Heath, Pilar Galan, Franck Georges, H. Robert Horvitz, Mark Lathrop, Shaun Purcell, Ammar Al-Chalabi, Robert H. Brown

Research output: Contribution to journalArticle

Abstract

Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genomewide significant result (P = 1.84 × 10 -8) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.

Original languageEnglish
Pages (from-to)9004-9009
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number22
DOIs
Publication statusPublished - Jun 2 2009

Keywords

  • Genome-wide association study
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • General

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    Landers, J. E., Melki, J., Meininger, V., Glass, J. D., Van Den Berg, L. H., Van Es, M. A., Sapp, P. C., Van Vught, P. W. J., McKenna-Yasek, D. M., Blauw, H. M., Cho, T. J., Polak, M., Shi, L., Wills, A. M., Broom, W. J., Ticozzi, N., Silani, V., Ozoguz, A., Rodriguez-Leyva, I., ... Brown, R. H. (2009). Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 106(22), 9004-9009. https://doi.org/10.1073/pnas.0812937106