Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort
Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort
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.
Amyotrophic lateral sclerosis, NIPA1, Repeat expansion
Tazelaar, Gijs H.P.
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Dekker, Annelot M.
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van Vugt, Joke J.F.A.
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van der Spek, Rick A.
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Westeneng, Henk Jan
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Kool, Lindy J.B.G.
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Kenna, Kevin P.
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van Rheenen, Wouter
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Pulit, Sara L.
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McLaughlin, Russell L.
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Sproviero, William
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Iacoangeli, Alfredo
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Hübers, Annemarie
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Brenner, David
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Morrison, Karen E.
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Shaw, Pamela J.
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Shaw, Christopher E.
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Panadés, Monica Povedano
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Mora Pardina, Jesus S.
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Glass, Jonathan D.
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Hardiman, Orla
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Al-Chalabi, Ammar
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van Damme, Philip
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Robberecht, Wim
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Landers, John E.
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Ludolph, Albert C.
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Weishaupt, Jochen H.
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van den Berg, Leonard H.
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Veldink, Jan H.
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van Es, Michael A.
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Project MinE ALS Sequencing Consortium
Tazelaar, Gijs H.P.
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Dekker, Annelot M.
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van Vugt, Joke J.F.A.
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van der Spek, Rick A.
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Westeneng, Henk Jan
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Kool, Lindy J.B.G.
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Kenna, Kevin P.
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van Rheenen, Wouter
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Pulit, Sara L.
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McLaughlin, Russell L.
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Sproviero, William
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Iacoangeli, Alfredo
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Hübers, Annemarie
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Brenner, David
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Morrison, Karen E.
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Shaw, Pamela J.
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Shaw, Christopher E.
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Panadés, Monica Povedano
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Mora Pardina, Jesus S.
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Glass, Jonathan D.
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Hardiman, Orla
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Al-Chalabi, Ammar
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van Damme, Philip
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Robberecht, Wim
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Landers, John E.
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Ludolph, Albert C.
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Weishaupt, Jochen H.
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van den Berg, Leonard H.
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Veldink, Jan H.
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van Es, Michael A.
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Tazelaar, Gijs H.P., Dekker, Annelot M., van Vugt, Joke J.F.A., van der Spek, Rick A., Westeneng, Henk Jan, Kool, Lindy J.B.G., Kenna, Kevin P., van Rheenen, Wouter, Pulit, Sara L., McLaughlin, Russell L., Sproviero, William, Iacoangeli, Alfredo, Hübers, Annemarie, Brenner, David, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Panadés, Monica Povedano, Mora Pardina, Jesus S., Glass, Jonathan D., Hardiman, Orla, Al-Chalabi, Ammar, van Damme, Philip, Robberecht, Wim, Landers, John E., Ludolph, Albert C., Weishaupt, Jochen H., van den Berg, Leonard H., Veldink, Jan H. and van Es, Michael A.
,
Project MinE ALS Sequencing Consortium
(2018)
Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort.
Neurobiology of Aging.
(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.
Text
NIPA1 NBA - manuscript
- Accepted Manuscript
Text
Supplmentary material - NIPA1 - NBA
- Accepted Manuscript
More information
Accepted/In Press date: 11 September 2018
e-pub ahead of print date: 22 September 2018
Keywords:
Amyotrophic lateral sclerosis, NIPA1, Repeat expansion
Identifiers
Local EPrints ID: 425865
URI: http://eprints.soton.ac.uk/id/eprint/425865
ISSN: 0197-4580
PURE UUID: 2bd7ecf4-1438-4a22-935b-60335a5f7e17
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Date deposited: 05 Nov 2018 17:30
Last modified: 06 Jun 2024 04:22
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Contributors
Author:
Gijs H.P. Tazelaar
Author:
Annelot M. Dekker
Author:
Joke J.F.A. van Vugt
Author:
Rick A. van der Spek
Author:
Henk Jan Westeneng
Author:
Lindy J.B.G. Kool
Author:
Kevin P. Kenna
Author:
Wouter van Rheenen
Author:
Sara L. Pulit
Author:
Russell L. McLaughlin
Author:
William Sproviero
Author:
Alfredo Iacoangeli
Author:
Annemarie Hübers
Author:
David Brenner
Author:
Karen E. Morrison
Author:
Pamela J. Shaw
Author:
Christopher E. Shaw
Author:
Monica Povedano Panadés
Author:
Jesus S. Mora Pardina
Author:
Jonathan D. Glass
Author:
Orla Hardiman
Author:
Ammar Al-Chalabi
Author:
Philip van Damme
Author:
Wim Robberecht
Author:
John E. Landers
Author:
Albert C. Ludolph
Author:
Jochen H. Weishaupt
Author:
Leonard H. van den Berg
Author:
Jan H. Veldink
Author:
Michael A. van Es
Corporate Author: Project MinE ALS Sequencing Consortium
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