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

• Type of Material: Article
• Authors: Gijs H. P. Tazelaar, University Medical Center Utrecht; Annelot M. Dekker, University Medical Center Utrecht; Joke J. F. A. van Vugt, University Medical Center Utrecht; Rick A. van der Spek, University Medical Center Utrecht; Henk-Jan Westeneng, University Medical Center Utrecht; Lindy J. B. G. Kool, University Medical Center Utrecht; Kevin P. Kenna, University Medical Center Utrecht; Wouter van Rheenen, University Medical Center Utrecht; Sara L. Pulit, University Medical Center Utrecht; Russell L. McLaughlin, Trinity College Dublin; William Sproviero, Kings College London; Alfredo Iacoangeli, Kings College London; Alfredo Huebers, Ulm University; David Brenner, Ulm University; Karen E. Morrison, University of Southampton; Pamela J. Shaw, University of Sheffield; Christopher E. Shaw, University of Sheffield; Monica Povedano Panades, Institute Carlos III; Jesus S. Mora Pardina, Hospital San Rafael; Jonathan Glass, Emory University; Orla Hardiman, Trinity College Dublin; Ammar Al-Chalabi, Kings College London; Philip van Damme, University of Leuven; Wim Robberecht, University of Leuven; John E. Landers, University of Massachusetts; Albert C. Ludolph, Ulm University; Jochen H. Weishaupt, Ulm University; Leonard H. van den Berg, University Medical Center Utrecht; Jan H. Veldink, University Medical Center Utrecht; Michael A. van Es, Univ Med Ctr Utrecht
• Language: English
• Date: 2019-02-01
• Publisher: Elsevier Science Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neurobiolaging.2018.09.012
• Title of Journal or Parent Work: Neurobiology of Aging
• Volume: 74
• Start Page: 234.e9
• End Page: 234.e15
• Grant/Funding Information: Research leading to these results has received funding from the European Community’s Health Seventh Framework Program (FP7/2007–2013).; This study was supported by the ALS Foundation Netherlands, the Belgian ALS Liga and National Lottery, and Agency for Innovation by Science and Technology (IWT), and the MND Association (UK) (Project MinE, www.projectmine.com).; C.E. Shaw and A Al-Chalabi receive salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Center in Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London.; This is an EU Joint Programme‒Neurodegenerative Disease Research (JPND) project (STRENGTH, MEND, SOPHIA, ALS-CarE).; The project is supported through the following funding organizations under the aegis of JPND: UK, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1); Ireland, Health Research Board; the Netherlands, ZonMw; Belgium, FWO-Vlaanderen.; P. Van Damme holds a senior clinical investigatorship from FWO-Vlaanderen.; M.A. van Es is supported by the Thierry Latran Foundation, the Dutch ALS foundation and the Rudolf Magnus Brain Center Talent Fellowship.; Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust.; This project was supported by the MND Association of England, Wales and Northern Ireland and the Netherlands Organisation for Health Research and Development (Vici scheme to L.H. van den Berg and veni scheme to M.A. van Es).; R.L. McLaughlin is supported by the Thierry Latran Foundation and the ALS Association (2284).; O. Hardiman is funded by the Health Research Board Clinician Scientist Program and Science Foundation Ireland. J.E. Landers is supported by the US National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (R01NS073873) and the American ALS Association.; This study was supported by ZonMW under the frame of E-Rare-2, the ERA Net for Research on Rare Diseases (PYRAMID).
• Keywords: Neurosciences & Neurology; Science & Technology; Amyotrophic lateral sclerosis; Genome; Repeat expansion; NIPA1; Geriatrics & Gerontology; Life Sciences & Biomedicine; Neurosciences; Hereditary spastic
• Research Categories: Gerontology; Health Sciences, Medicine and Surgery; Biology, Neuroscience

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.