Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Aude Nicolas; Kevin P. Kenna; Alan E. Renton; Nicola Ticozzi; Faraz Faghri; Ruth Chia; Janice A. Dominov; Brendan J. Kenna; Mike A. Nalls; Pamela Keagle; Alberto M. Rivera; Wouter van Rheenen; Natalie A. Murphy; Joke J.F.A. van Vugt; Joshua T. Geiger; Rick van der Spek; Hannah A. Pliner; Shankaracharya [Unknown]; Bradley N. Smith; Giuseppe Marangi; Simon D. Topp; Yevgeniya Abramzon; Athina Soragia Gkazi; John D. Eicher; Aoife Kenna; Francesco O. Logullo; Isabella Simone; Giancarlo Logroscino; Fabrizio Salvi; Ilaria Bartolomei; Giuseppe Borghero; Maria Rita Murru; Emanuela Costantino; Carla Pani; Roberta Puddu; Carla Caredda; Valeria Piras; Pietro Fratta; Isabella Fogh; Safa Al-Sarraj; Claire Troakes; Caroline Vance; Aleksey Shatunov; Ammar Al-Chalabi; Alfredo Iacoangeli; Stephen Newhouse; Chris Shaw; William Sproviero; Christopher E. Shaw; ITALSGEN Consortium; Genomic Translation for ALS Care (GTAC) Consortium; NYGC ALS Consortium; Answer ALS Foundation; Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium; SLAGEN Consortium; French ALS Consortium; Project MinE ALS Sequencing Consortium; Ahmad Al Khleifat

doi:10.1016/j.neuron.2018.02.027

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick van der Spek, Hannah A. Pliner, Shankaracharya [Unknown], Bradley N. Smith, Giuseppe MarangiSimon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Francesco O. Logullo, Isabella Simone, Giancarlo Logroscino, Fabrizio Salvi, Ilaria Bartolomei, Giuseppe Borghero, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Pietro Fratta, Isabella Fogh, Safa Al-Sarraj, Claire Troakes, Caroline Vance, Aleksey Shatunov, Ammar Al-Chalabi, Alfredo Iacoangeli, Stephen Newhouse, Chris Shaw, William Sproviero, Christopher E. Shaw, ITALSGEN Consortium, Genomic Translation for ALS Care (GTAC) Consortium, NYGC ALS Consortium, Answer ALS Foundation, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consortium, Ahmad Al Khleifat

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

338 Citations (Scopus)

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Original language	English
Pages (from-to)	1268
Number of pages	1
Journal	Neuron
Volume	97
Issue number	6
Early online date	21 Mar 2018
DOIs	https://doi.org/10.1016/j.neuron.2018.02.027
Publication status	E-pub ahead of print - 21 Mar 2018

Keywords

ALS
KIF5A
GWAS
WES
WGS
cargo
axonal transport

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Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., van der Spek, R., Pliner, H. A., [Unknown], S., Smith, B. N., ... Al Khleifat, A. (2018). Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97(6), 1268. https://doi.org/10.1016/j.neuron.2018.02.027

@article{7e5ff19418a34c7aabccdacd0ab50755,

title = "Genome-wide Analyses Identify KIF5A as a Novel ALS Gene",

abstract = "To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.",

keywords = "ALS, KIF5A, GWAS, WES, WGS, cargo, axonal transport",

author = "Aude Nicolas and Kenna, {Kevin P.} and Renton, {Alan E.} and Nicola Ticozzi and Faraz Faghri and Ruth Chia and Dominov, {Janice A.} and Kenna, {Brendan J.} and Nalls, {Mike A.} and Pamela Keagle and Rivera, {Alberto M.} and {van Rheenen}, Wouter and Murphy, {Natalie A.} and {van Vugt}, {Joke J.F.A.} and Geiger, {Joshua T.} and {van der Spek}, Rick and Pliner, {Hannah A.} and Shankaracharya [Unknown] and Smith, {Bradley N.} and Giuseppe Marangi and Topp, {Simon D.} and Yevgeniya Abramzon and Gkazi, {Athina Soragia} and Eicher, {John D.} and Aoife Kenna and Logullo, {Francesco O.} and Isabella Simone and Giancarlo Logroscino and Fabrizio Salvi and Ilaria Bartolomei and Giuseppe Borghero and Murru, {Maria Rita} and Emanuela Costantino and Carla Pani and Roberta Puddu and Carla Caredda and Valeria Piras and Pietro Fratta and Isabella Fogh and Safa Al-Sarraj and Claire Troakes and Caroline Vance and Aleksey Shatunov and Ammar Al-Chalabi and Alfredo Iacoangeli and Stephen Newhouse and Chris Shaw and William Sproviero and Shaw, {Christopher E.} and {ITALSGEN Consortium} and {Genomic Translation for ALS Care (GTAC) Consortium} and {NYGC ALS Consortium} and {Answer ALS Foundation} and {Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium} and {SLAGEN Consortium} and {French ALS Consortium} and {Project MinE ALS Sequencing Consortium} and {Al Khleifat}, Ahmad",

year = "2018",

month = mar,

day = "21",

doi = "10.1016/j.neuron.2018.02.027",

language = "English",

volume = "97",

pages = "1268",

journal = "Neuron",

issn = "0896-6273",

publisher = "CELL PRESS",

number = "6",

}

Nicolas, A, Kenna, KP, Renton, AE, Ticozzi, N, Faghri, F, Chia, R, Dominov, JA, Kenna, BJ, Nalls, MA, Keagle, P, Rivera, AM, van Rheenen, W, Murphy, NA, van Vugt, JJFA, Geiger, JT, van der Spek, R, Pliner, HA, [Unknown], S, Smith, BN, Marangi, G, Topp, SD, Abramzon, Y, Gkazi, AS, Eicher, JD, Kenna, A, Logullo, FO, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, MR, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Fratta, P , Fogh, I , Al-Sarraj, S , Troakes, C , Vance, C , Shatunov, A , Al-Chalabi, A , Iacoangeli, A , Newhouse, S , Shaw, C , Sproviero, W , Shaw, CE, ITALSGEN Consortium, Genomic Translation for ALS Care (GTAC) Consortium, NYGC ALS Consortium, Answer ALS Foundation, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consortium & Al Khleifat, A 2018, 'Genome-wide Analyses Identify KIF5A as a Novel ALS Gene', Neuron, vol. 97, no. 6, pp. 1268. https://doi.org/10.1016/j.neuron.2018.02.027

TY - JOUR

T1 - Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

AU - Nicolas, Aude

AU - Kenna, Kevin P.

AU - Renton, Alan E.

AU - Ticozzi, Nicola

AU - Faghri, Faraz

AU - Chia, Ruth

AU - Dominov, Janice A.

AU - Kenna, Brendan J.

AU - Nalls, Mike A.

AU - Keagle, Pamela

AU - Rivera, Alberto M.

AU - van Rheenen, Wouter

AU - Murphy, Natalie A.

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

AU - Geiger, Joshua T.

AU - van der Spek, Rick

AU - Pliner, Hannah A.

AU - [Unknown], Shankaracharya

AU - Smith, Bradley N.

AU - Marangi, Giuseppe

AU - Topp, Simon D.

AU - Abramzon, Yevgeniya

AU - Gkazi, Athina Soragia

AU - Eicher, John D.

AU - Kenna, Aoife

AU - Logullo, Francesco O.

AU - Simone, Isabella

AU - Logroscino, Giancarlo

AU - Salvi, Fabrizio

AU - Bartolomei, Ilaria

AU - Borghero, Giuseppe

AU - Murru, Maria Rita

AU - Costantino, Emanuela

AU - Pani, Carla

AU - Puddu, Roberta

AU - Caredda, Carla

AU - Piras, Valeria

AU - Fratta, Pietro

AU - Fogh, Isabella

AU - Al-Sarraj, Safa

AU - Troakes, Claire

AU - Vance, Caroline

AU - Shatunov, Aleksey

AU - Al-Chalabi, Ammar

AU - Iacoangeli, Alfredo

AU - Newhouse, Stephen

AU - Shaw, Chris

AU - Sproviero, William

AU - Shaw, Christopher E.

AU - ITALSGEN Consortium

AU - Genomic Translation for ALS Care (GTAC) Consortium

AU - NYGC ALS Consortium

AU - Answer ALS Foundation

AU - Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium

AU - SLAGEN Consortium

AU - French ALS Consortium

AU - Project MinE ALS Sequencing Consortium

AU - Al Khleifat, Ahmad

PY - 2018/3/21

Y1 - 2018/3/21

N2 - To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

AB - To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

KW - ALS

KW - KIF5A

KW - GWAS

KW - WES

KW - WGS

KW - cargo

KW - axonal transport

U2 - 10.1016/j.neuron.2018.02.027

DO - 10.1016/j.neuron.2018.02.027

M3 - Article

SN - 0896-6273

VL - 97

SP - 1268

JO - Neuron

JF - Neuron

IS - 6

ER -

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Abstract

Keywords

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