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

Gijs HP. Tazelaar, Annelot M. Dekker, Joke JFA. van Vugt, Rick A. van der Spek, Henk-Jan Westeneng, Lindy JBG. 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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NIPA1 (non-imprinted 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. Previously, a genome-wide 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 3,955 ALS patients and 2,276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6,245 ALS patients and 5,051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG-repeat length (odds ratio = 1.50, P = 3.8x10-5). 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
Early online date22 Sept 2018
Publication statusE-pub ahead of print - 22 Sept 2018


  • Amyotrophic lateral sclerosis
  • NIPA1
  • Repeat expansion


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