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

Gijs H P Tazelaar¹, Annelot M Dekker¹, Joke J F A van Vugt¹, Rick A van der Spek¹, Henk-Jan Westeneng¹, Lindy J B G Kool¹, Kevin P Kenna¹, Wouter van Rheenen¹, Sara L Pulit¹, Russell L McLaughlin², William Sproviero³, Alfredo Iacoangeli⁴, Annemarie Hübers⁵, David Brenner⁵, Karen E Morrison⁶, Pamela J Shaw⁷, Christopher E Shaw⁷, Monica Povedano Panadés⁸, Jesus S Mora Pardina⁹, Jonathan D Glass¹⁰, Orla Hardiman¹¹, Ammar Al-Chalabi¹², Philip van Damme¹³, Wim Robberecht¹³, John E Landers¹⁴, Albert C Ludolph⁵, Jochen H Weishaupt⁵, Leonard H van den Berg¹, Jan H Veldink¹, Michael A van Es¹⁵; Project MinE ALS Sequencing Consortium

Affiliations

¹ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
² Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Republic of Ireland.
³ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King's College London, London, UK.
⁴ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵ Department of Neurology, Ulm University, Ulm, Germany.
⁶ Faculty of Medicine, University of Southampton, Southampton, UK.
⁷ Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
⁸ Biomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Hospitalet de Llobregat, Spain; Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
⁹ ALS Unit, Hospital San Rafael, Madrid, Spain.
¹⁰ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Emory ALS Center, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Republic of Ireland; Department of Neurology, Beaumont Hospital, Dublin, Republic of Ireland.
¹² Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King's College London, London, UK; Department of Neurology, King's College Hospital, London, UK.
¹³ KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium; VIB, Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
¹⁴ Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
¹⁵ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: M.A.vanEs@umcutrecht.nl.

PMID: 30342764
PMCID: PMC7893598
DOI: 10.1016/j.neurobiolaging.2018.09.012

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

Gijs H P Tazelaar et al. Neurobiol Aging. 2019 Feb.

. 2019 Feb:74:234.e9-234.e15.

doi: 10.1016/j.neurobiolaging.2018.09.012. Epub 2018 Sep 22.

Authors

Affiliations

¹ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
² Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Republic of Ireland.
³ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King's College London, London, UK.
⁴ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵ Department of Neurology, Ulm University, Ulm, Germany.
⁶ Faculty of Medicine, University of Southampton, Southampton, UK.
⁷ Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
⁸ Biomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Hospitalet de Llobregat, Spain; Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
⁹ ALS Unit, Hospital San Rafael, Madrid, Spain.
¹⁰ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Emory ALS Center, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Republic of Ireland; Department of Neurology, Beaumont Hospital, Dublin, Republic of Ireland.
¹² Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King's College London, London, UK; Department of Neurology, King's College Hospital, London, UK.
¹³ KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium; VIB, Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
¹⁴ Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
¹⁵ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: M.A.vanEs@umcutrecht.nl.

PMID: 30342764
PMCID: PMC7893598
DOI: 10.1016/j.neurobiolaging.2018.09.012

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.

Keywords: Amyotrophic lateral sclerosis; NIPA1; Repeat expansion.

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Figures

**Fig. 1.**
*NIPA1* polyalanine repeat length distribution. Proportion of total alleles grouped per *NIPA1* polyalanine repeat size. Alleles displayed were observed multiple times in the Dutch replication cohort of 1517 individuals affected with amyotrophic lateral sclerosis (blue) and 1370 unaffected controls (orange).

**Fig. 2.**
*NIPA1* polyalanine repeat expansion meta-analysis. Forest plot for the fixed-effect meta-analysis and joint analysis on individual level data of the effect of expanded *NIPA1* polyalanine (>8 GCG repeats) on amyotrophic lateral sclerosis risk with the initial discovery reports (Blauw et al., 2012) and current replication using PCR, Sanger, or whole-genome sequencing (WGS) grouped per cohort/country of origin. Weights depending on number of participants. CI, confidence interval.

See this image and copyright information in PMC

References

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

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

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