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. Glass; Orla 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

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, 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

27 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 language	English
Pages (from-to)	234.e9-234.e15
Number of pages	7
Journal	Neurobiology of Aging
Volume	74
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.09.012
Publication status	Published - 1 Feb 2019

Keywords

Amyotrophic lateral sclerosis
NIPA1
Repeat expansion

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10.1016/j.neurobiolaging.2018.09.012

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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., ... Project MinE ALS Sequencing Consortium (2019). Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort. Neurobiology of Aging, 74, 234.e9-234.e15. https://doi.org/10.1016/j.neurobiolaging.2018.09.012

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title = "Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort",

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",

author = "Tazelaar, {Gijs H. P.} and Dekker, {Annelot M.} and {van Vugt}, {Joke J. F. A.} and {van der Spek}, {Rick A.} and Henk-Jan Westeneng and Kool, {Lindy J. B. G.} and Kenna, {Kevin P.} and {van Rheenen}, Wouter and Pulit, {Sara L.} and McLaughlin, {Russell L.} and William Sproviero and Alfredo Iacoangeli and Annemarie H{\"u}bers and David Brenner and Morrison, {Karen E.} and Shaw, {Pamela J.} and Shaw, {Christopher E.} and Panad{\'e}s, {Monica Povedano} and {Mora Pardina}, {Jesus S.} and Glass, {Jonathan D.} and Orla Hardiman and Ammar Al-Chalabi and {van Damme}, Philip and Wim Robberecht and Landers, {John E.} and Ludolph, {Albert C.} and Weishaupt, {Jochen H.} and {van den Berg}, {Leonard H.} and Veldink, {Jan H.} and {van Es}, {Michael A.} and {Project MinE ALS Sequencing Consortium} and Fulya Akcimen and {Al Khleifat}, Ahmad and Peter Anderson and Basak, {A. Nazli} and Bauer, {Denis C.} and Ian Blair and Brands, {William J.} and Byrne, {Ross P.} and Andrea Calvo and {Campos Gonzalez}, Yolanda and Adriano Chio and Jonothan Cooper-Knock and Philippe Corcia and Philippe Couratier and Carvalho, {Mamede de} and Dekker, {Annelot M.} and Drory, {Vivian E.} and Chen Eitan and Alberto Garc{\'i}a-Redondo and Cinzia Gellera and Marc Gotkine and Eran Hornstein and Brendan Kenna and Kiernan, {Matthew C.} and Cemile Kocoglu and Maarten Kooyman and {L{\'o}pez Alonso}, Victoria and Bas Middelkoop and Jonathan Mill and Miguel Mitne-Neto and Matthieu Moisse and Pinto, {Susana C.} and Antonia Ratti and Schellevis, {Raymond D.} and Aleksey Shatunov and Vincenzo Silani and Christine Staiger and Nicola Ticozzi and Ceren Tunca and Twine, {Nathalie A.} and {van Doormaal}, {Perry T. C.} and {van Eijk}, {Kristel R.} and Visscher, {Peter M.} and Patrick Vourc{\textquoteright}h and Markus Weber and Williams, {Kelly L.} and Naomi Wray and Jian Yang and Mayana Zatz and Katharine Zhang",

year = "2019",

month = feb,

day = "1",

doi = "10.1016/j.neurobiolaging.2018.09.012",

language = "English",

volume = "74",

pages = "234.e9--234.e15",

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Tazelaar, GHP, Dekker, AM, van Vugt, JJFA, van der Spek, RA, Westeneng, H-J, Kool, LJBG, Kenna, KP, van Rheenen, W, Pulit, SL, McLaughlin, RL, Sproviero, W, Iacoangeli, A, Hübers, A, Brenner, D, Morrison, KE, Shaw, PJ, Shaw, CE, Panadés, MP, Mora Pardina, JS, Glass, JD, Hardiman, O, Al-Chalabi, A, van Damme, P, Robberecht, W, Landers, JE, Ludolph, AC, Weishaupt, JH, van den Berg, LH, Veldink, JH, van Es, MA & Project MinE ALS Sequencing Consortium 2019, 'Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort', Neurobiology of Aging, vol. 74, pp. 234.e9-234.e15. https://doi.org/10.1016/j.neurobiolaging.2018.09.012

TY - JOUR

T1 - Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort

AU - Tazelaar, Gijs H. P.

AU - Dekker, Annelot M.

AU - van Vugt, Joke J. F. A.

AU - van der Spek, Rick A.

AU - Westeneng, Henk-Jan

AU - Kool, Lindy J. B. G.

AU - Kenna, Kevin P.

AU - van Rheenen, Wouter

AU - Pulit, Sara L.

AU - McLaughlin, Russell L.

AU - Sproviero, William

AU - Iacoangeli, Alfredo

AU - Hübers, Annemarie

AU - Brenner, David

AU - Morrison, Karen E.

AU - Shaw, Pamela J.

AU - Shaw, Christopher E.

AU - Panadés, Monica Povedano

AU - Mora Pardina, Jesus S.

AU - Glass, Jonathan D.

AU - Hardiman, Orla

AU - Al-Chalabi, Ammar

AU - van Damme, Philip

AU - Robberecht, Wim

AU - Landers, John E.

AU - Ludolph, Albert C.

AU - Weishaupt, Jochen H.

AU - van den Berg, Leonard H.

AU - Veldink, Jan H.

AU - van Es, Michael A.

AU - Project MinE ALS Sequencing Consortium

AU - Akcimen, Fulya

AU - Al Khleifat, Ahmad

AU - Anderson, Peter

AU - Basak, A. Nazli

AU - Bauer, Denis C.

AU - Blair, Ian

AU - Brands, William J.

AU - Byrne, Ross P.

AU - Calvo, Andrea

AU - Campos Gonzalez, Yolanda

AU - Chio, Adriano

AU - Cooper-Knock, Jonothan

AU - Corcia, Philippe

AU - Couratier, Philippe

AU - Carvalho, Mamede de

AU - Dekker, Annelot M.

AU - Drory, Vivian E.

AU - Eitan, Chen

AU - García-Redondo, Alberto

AU - Gellera, Cinzia

AU - Gotkine, Marc

AU - Hornstein, Eran

AU - Kenna, Brendan

AU - Kiernan, Matthew C.

AU - Kocoglu, Cemile

AU - Kooyman, Maarten

AU - López Alonso, Victoria

AU - Middelkoop, Bas

AU - Mill, Jonathan

AU - Mitne-Neto, Miguel

AU - Moisse, Matthieu

AU - Pinto, Susana C.

AU - Ratti, Antonia

AU - Schellevis, Raymond D.

AU - Shatunov, Aleksey

AU - Silani, Vincenzo

AU - Staiger, Christine

AU - Ticozzi, Nicola

AU - Tunca, Ceren

AU - Twine, Nathalie A.

AU - van Doormaal, Perry T. C.

AU - van Eijk, Kristel R.

AU - Visscher, Peter M.

AU - Vourc’h, Patrick

AU - Weber, Markus

AU - Williams, Kelly L.

AU - Wray, Naomi

AU - Yang, Jian

AU - Zatz, Mayana

AU - Zhang, Katharine

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - NIPA1

KW - Repeat expansion

UR - http://www.scopus.com/inward/record.url?scp=85054853443&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2018.09.012

DO - 10.1016/j.neurobiolaging.2018.09.012

M3 - Article

C2 - 30342764

AN - SCOPUS:85054853443

SN - 0197-4580

VL - 74

SP - 234.e9-234.e15

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

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Keywords

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