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

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,

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

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
Journal	Neurobiology of Aging
Volume	74
Early online date	22 Sept 2018
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.09.012
Publication status	Published - Feb 2019

Keywords

NIPA1
Amyotrophic lateral sclerosis
Repeat expansion
DNA Repeat Expansion/genetics
Meta-Analysis as Topic
Genetic Association Studies
Humans
Membrane Proteins/genetics
Logistic Models
Male
Amyotrophic Lateral Sclerosis/genetics
Peptides/genetics
Internationality
Female
Cohort Studies

Access to Document

10.1016/j.neurobiolaging.2018.09.012

Cite this

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. (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

@article{346b06e18c7642a79ff388bf24b4d895,

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 = "NIPA1, Amyotrophic lateral sclerosis, Repeat expansion, DNA Repeat Expansion/genetics, Meta-Analysis as Topic, Genetic Association Studies, Humans, Membrane Proteins/genetics, Logistic Models, Male, Amyotrophic Lateral Sclerosis/genetics, Peptides/genetics, Internationality, Female, Cohort Studies",

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}",

note = "Funding Information: L.H. van den Berg serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen, and Cytokinetics; and serves on the editorial board of Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration and the Journal of Neurology, Neurosurgery, and Psychiatry. O. Hardiman has received speaking honoraria from Novarits, Biogen Idec, Sanofi Aventis, and Merck-Serono; has been a member of advisory panels for Biogen Idec, Allergen, Ono Pharmaceuticals, Novartis, Cytokinetics, and Sanofi Aventis; and serves as the editor-in-chief of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. A. Al-Chalabi has consulted for OrionPharma, Biogen Idec, Cytokinetics Inc, Treeway Inc, and Chronos Therapeutics. J.H. Veldink reports that his institute received consultancy fees from Vertex Pharmaceuticals outside the submitted work. M.A. van Es received grants from the Netherlands Organization for Health Research and Development (Veni scheme), the Thierry Latran foundation, the Netherlands ALS foundation (Stichting ALS Nederland), and the Joint Program Neurodegeneration (JPND). He has received travel grants from Baxalta and serves on the biomedical research advisory panel of the motor neurone disease association (MNDA). Other authors have no reported conflicts of interest. Funding Information: 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). 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 ZonMW under the frame of E-Rare-2, the ERA Net for Research on Rare Diseases (PYRAMID). 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. 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). NDAL cordially thanks Suna and Inan Kirac Foundation for their generous support. M.A. van Es is supported by the Thierry Latran Foundation, the Dutch ALS foundation and the Rudolf Magnus Brain Center Talent Fellowship. 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. 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. R.L. McLaughlin is supported by the Thierry Latran Foundation and the ALS Association (2284). P. Van Damme holds a senior clinical investigatorship from FWO-Vlaanderen. Funding Information: 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 ). 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 ZonMW under the frame of E-Rare-2 , the ERA Net for Research on Rare Diseases (PYRAMID) . 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. 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). NDAL cordially thanks Suna and Inan Kirac Foundation for their generous support. M.A. van Es is supported by the Thierry Latran Foundation, the Dutch ALS foundation and the Rudolf Magnus Brain Center Talent Fellowship. 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. 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. R.L. McLaughlin is supported by the Thierry Latran Foundation and the ALS Association ( 2284 ). P. Van Damme holds a senior clinical investigatorship from FWO-Vlaanderen. Funding Information: 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). 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 ZonMW under the frame of E-Rare-2, the ERA Net for Research on Rare Diseases (PYRAMID). 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. 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). NDAL cordially thanks Suna and Inan Kirac Foundation for their generous support. M.A. van Es is supported by the Thierry Latran Foundation, the Dutch ALS foundation and the Rudolf Magnus Brain Center Talent Fellowship. 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. 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. R.L. McLaughlin is supported by the Thierry Latran Foundation and the ALS Association (2284). P. Van Damme holds a senior clinical investigatorship from FWO-Vlaanderen. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

month = feb,

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

language = "English",

volume = "74",

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

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier",

}

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 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

N1 - Funding Information: L.H. van den Berg serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen, and Cytokinetics; and serves on the editorial board of Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration and the Journal of Neurology, Neurosurgery, and Psychiatry. O. Hardiman has received speaking honoraria from Novarits, Biogen Idec, Sanofi Aventis, and Merck-Serono; has been a member of advisory panels for Biogen Idec, Allergen, Ono Pharmaceuticals, Novartis, Cytokinetics, and Sanofi Aventis; and serves as the editor-in-chief of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. A. Al-Chalabi has consulted for OrionPharma, Biogen Idec, Cytokinetics Inc, Treeway Inc, and Chronos Therapeutics. J.H. Veldink reports that his institute received consultancy fees from Vertex Pharmaceuticals outside the submitted work. M.A. van Es received grants from the Netherlands Organization for Health Research and Development (Veni scheme), the Thierry Latran foundation, the Netherlands ALS foundation (Stichting ALS Nederland), and the Joint Program Neurodegeneration (JPND). He has received travel grants from Baxalta and serves on the biomedical research advisory panel of the motor neurone disease association (MNDA). Other authors have no reported conflicts of interest. Funding Information: 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). 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 ZonMW under the frame of E-Rare-2, the ERA Net for Research on Rare Diseases (PYRAMID). 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. 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). NDAL cordially thanks Suna and Inan Kirac Foundation for their generous support. M.A. van Es is supported by the Thierry Latran Foundation, the Dutch ALS foundation and the Rudolf Magnus Brain Center Talent Fellowship. 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. 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. R.L. McLaughlin is supported by the Thierry Latran Foundation and the ALS Association (2284). P. Van Damme holds a senior clinical investigatorship from FWO-Vlaanderen. Funding Information: 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 ). 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 ZonMW under the frame of E-Rare-2 , the ERA Net for Research on Rare Diseases (PYRAMID) . 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. 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). NDAL cordially thanks Suna and Inan Kirac Foundation for their generous support. M.A. van Es is supported by the Thierry Latran Foundation, the Dutch ALS foundation and the Rudolf Magnus Brain Center Talent Fellowship. 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. 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. R.L. McLaughlin is supported by the Thierry Latran Foundation and the ALS Association ( 2284 ). P. Van Damme holds a senior clinical investigatorship from FWO-Vlaanderen. Funding Information: 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). 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 ZonMW under the frame of E-Rare-2, the ERA Net for Research on Rare Diseases (PYRAMID). 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. 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). NDAL cordially thanks Suna and Inan Kirac Foundation for their generous support. M.A. van Es is supported by the Thierry Latran Foundation, the Dutch ALS foundation and the Rudolf Magnus Brain Center Talent Fellowship. 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. 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. R.L. McLaughlin is supported by the Thierry Latran Foundation and the ALS Association (2284). P. Van Damme holds a senior clinical investigatorship from FWO-Vlaanderen. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2019/2

Y1 - 2019/2

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 - NIPA1

KW - Amyotrophic lateral sclerosis

KW - Repeat expansion

KW - DNA Repeat Expansion/genetics

KW - Meta-Analysis as Topic

KW - Genetic Association Studies

KW - Humans

KW - Membrane Proteins/genetics

KW - Logistic Models

KW - Male

KW - Amyotrophic Lateral Sclerosis/genetics

KW - Peptides/genetics

KW - Internationality

KW - Female

KW - Cohort Studies

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

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this