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. 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 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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Abstract

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 language	English
Journal	Neurobiology of Aging
Early online date	22 Sept 2018
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.09.012
Publication status	E-pub ahead of print - 22 Sept 2018

Keywords

Amyotrophic lateral sclerosis
NIPA1
Repeat expansion

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10.1016/j.neurobiolaging.2018.09.012

Association of NIPA1 repeat_TAZELAAR_Firstonline22September2018_GREEN AAM (CC BY-NC-ND)Accepted author manuscript, 538 KBLicence: CC BY-NC-ND

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Tazelaar, G. HP., Dekker, A. M., van Vugt, J. JFA., van der Spek, R. A., Westeneng, H.-J., Kool, L. JBG., 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 (2018). Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort. Neurobiology of Aging. Advance online publication. https://doi.org/10.1016/j.neurobiolaging.2018.09.012

@article{5b8fd6bbfa814d7c9b6bfe2de4a9620a,

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

abstract = "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.",

keywords = "Amyotrophic lateral sclerosis, NIPA1, Repeat expansion",

author = "Tazelaar, {Gijs HP.} and Dekker, {Annelot M.} and {van Vugt}, {Joke JFA.} and {van der Spek}, {Rick A.} and Henk-Jan Westeneng and Kool, {Lindy JBG.} 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}",

year = "2018",

month = sep,

day = "22",

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

language = "English",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier B.V.",

}

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 2018, 'Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort', Neurobiology of Aging. 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 HP.

AU - Dekker, Annelot M.

AU - van Vugt, Joke JFA.

AU - van der Spek, Rick A.

AU - Westeneng, Henk-Jan

AU - Kool, Lindy JBG.

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

PY - 2018/9/22

Y1 - 2018/9/22

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - NIPA1

KW - Repeat expansion

U2 - 10.1016/j.neurobiolaging.2018.09.012

DO - 10.1016/j.neurobiolaging.2018.09.012

M3 - Article

SN - 0197-4580

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

Abstract

Keywords

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