Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort

Gijs H.P. Tazelaar, Annelot M. Dekker, Joke J.F.A. van Vugt, Rick A. van der Spek, Henk Jan Westeneng, Lindy J.B.G. Kool, Kevin P. Kenna, Wouter van Rheenen, Sara L. Pulit, Russell L. McLaughlin, William Sproviero, Alfredo Iacoangeli, Annemarie Hübers, David Brenner, Karen E. Morrison, Pamela J. Shaw, Christopher E. Shaw, Monica Povedano Panadés, Jesus S. Mora Pardina, Jonathan D. GlassOrla Hardiman, Ammar Al-Chalabi, Philip van Damme, Wim Robberecht, John E. Landers, Albert C. Ludolph, Jochen H. Weishaupt, Leonard H. van den Berg, Jan H. Veldink, Michael A. van Es, Project MinE ALS Sequencing Consortium

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6 Citations (Scopus)

Abstract

NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10−5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.
Original languageEnglish
JournalNeurobiology of Aging
DOIs
Publication statusPublished - 22 Sep 2018

Keywords

  • Amyotrophic lateral sclerosis
  • NIPA1
  • Repeat expansion

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    Tazelaar, G. H. P., Dekker, A. M., van Vugt, J. J. F. A., van der Spek, R. A., Westeneng, H. J., Kool, L. J. B. G., Kenna, K. P., van Rheenen, W., Pulit, S. L., McLaughlin, R. L., Sproviero, W., Iacoangeli, A., Hübers, A., Brenner, D., Morrison, K. E., Shaw, P. J., Shaw, C. E., Panadés, M. P., Mora Pardina, J. S., ... Consortium, P. M. ALS. S. (2018). Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort. Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2018.09.012