Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Elizabeth T. Cirulli; Brittany N. Lasseigne; Slavé Petrovski; Peter C. Sapp; Patrick A. Dion; Claire S. Leblond; Julien Couthouis; Yi Fan Lu; Quanli Wang; Brian J. Krueger; Zhong Ren; Jonathan Keebler; Yujun Han; Shawn E. Levy; Braden E. Boone; Jack R. Wimbish; Lindsay L. Waite; Angela L. Jones; John P. Carulli; Aaron G. Day-Williams; John F. Staropoli; Winnie W. Xin; Alessandra Chesi; Alya R. Raphael; Diane McKenna-Yasek; Janet Cady; J. M B Vianney De Jong; Kevin P. Kenna; Bradley N. Smith; Simon Topp; Jack Miller; Athina Gkazi; Ammar Al-Chalabi; Leonard H. Van Den Berg; Jan Veldink; Vincenzo Silani; Nicola Ticozzi; Christopher E. Shaw; Robert H. Baloh; Stanley Appel; Ericka Simpson; Clotilde Lagier-Tourenne; Stefan M. Pulst; Summer Gibson; John Q. Trojanowski; Lauren Elman; Leo McCluskey; Murray Grossman; Neil A. Shneider; Wendy K. Chung; John M. Ravits; Jonathan D. Glass; Katherine B. Sims; Vivianna M. Van Deerlin; Tom Maniatis; Sebastian D. Hayes; Alban Ordureau; Sharan Swarup; John Landers; Frank Baas; Andrew S. Allen; Richard S. Bedlack; J. Wade Harper; Aaron D. Gitler; Guy A. Rouleau; Robert Brown; Matthew B. Harms; Gregory M. Cooper; Tim Harris; Richard M. Myers; David B. Goldstein

doi:10.1126/science.aaa3650

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Elizabeth T. Cirulli, Brittany N. Lasseigne, Slavé Petrovski, Peter C. Sapp, Patrick A. Dion, Claire S. Leblond, Julien Couthouis, Yi Fan Lu, Quanli Wang, Brian J. Krueger, Zhong Ren, Jonathan Keebler, Yujun Han, Shawn E. Levy, Braden E. Boone, Jack R. Wimbish, Lindsay L. Waite, Angela L. Jones, John P. Carulli, Aaron G. Day-WilliamsJohn F. Staropoli, Winnie W. Xin, Alessandra Chesi, Alya R. Raphael, Diane McKenna-Yasek, Janet Cady, J. M B Vianney De Jong, Kevin P. Kenna, Bradley N. Smith, Simon Topp, Jack Miller, Athina Gkazi, Ammar Al-Chalabi, Leonard H. Van Den Berg, Jan Veldink, Vincenzo Silani, Nicola Ticozzi, Christopher E. Shaw, Robert H. Baloh, Stanley Appel, Ericka Simpson, Clotilde Lagier-Tourenne, Stefan M. Pulst, Summer Gibson, John Q. Trojanowski, Lauren Elman, Leo McCluskey, Murray Grossman, Neil A. Shneider, Wendy K. Chung, John M. Ravits, Jonathan D. Glass, Katherine B. Sims, Vivianna M. Van Deerlin, Tom Maniatis, Sebastian D. Hayes, Alban Ordureau, Sharan Swarup, John Landers, Frank Baas, Andrew S. Allen, Richard S. Bedlack, J. Wade Harper, Aaron D. Gitler, Guy A. Rouleau, Robert Brown, Matthew B. Harms, Gregory M. Cooper, Tim Harris, Richard M. Myers, David B. Goldstein

Fondazione Istituto Auxologico Italiano

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

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment.We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

Original language	English
Pages (from-to)	1436-1441
Number of pages	6
Journal	Science
Volume	347
Issue number	6229
DOIs	https://doi.org/10.1126/science.aaa3650
Publication status	Published - Mar 27 2015

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Cirulli, E. T., Lasseigne, B. N., Petrovski, S., Sapp, P. C., Dion, P. A., Leblond, C. S., Couthouis, J., Lu, Y. F., Wang, Q., Krueger, B. J., Ren, Z., Keebler, J., Han, Y., Levy, S. E., Boone, B. E., Wimbish, J. R., Waite, L. L., Jones, A. L., Carulli, J. P., ... Goldstein, D. B. (2015). Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science, 347(6229), 1436-1441. https://doi.org/10.1126/science.aaa3650

Cirulli, ET, Lasseigne, BN, Petrovski, S, Sapp, PC, Dion, PA, Leblond, CS, Couthouis, J, Lu, YF, Wang, Q, Krueger, BJ, Ren, Z, Keebler, J, Han, Y, Levy, SE, Boone, BE, Wimbish, JR, Waite, LL, Jones, AL, Carulli, JP, Day-Williams, AG, Staropoli, JF, Xin, WW, Chesi, A, Raphael, AR, McKenna-Yasek, D, Cady, J, De Jong, JMBV, Kenna, KP, Smith, BN, Topp, S, Miller, J, Gkazi, A, Al-Chalabi, A, Van Den Berg, LH, Veldink, J, Silani, V , Ticozzi, N, Shaw, CE, Baloh, RH, Appel, S, Simpson, E, Lagier-Tourenne, C, Pulst, SM, Gibson, S, Trojanowski, JQ, Elman, L, McCluskey, L, Grossman, M, Shneider, NA, Chung, WK, Ravits, JM, Glass, JD, Sims, KB, Van Deerlin, VM, Maniatis, T, Hayes, SD, Ordureau, A, Swarup, S, Landers, J, Baas, F, Allen, AS, Bedlack, RS, Harper, JW, Gitler, AD, Rouleau, GA, Brown, R, Harms, MB, Cooper, GM, Harris, T, Myers, RM & Goldstein, DB 2015, 'Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways', Science, vol. 347, no. 6229, pp. 1436-1441. https://doi.org/10.1126/science.aaa3650

@article{8d3cd686912d430983ec584583a86583,

title = "Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways",

abstract = "Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment.We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.",

author = "Cirulli, {Elizabeth T.} and Lasseigne, {Brittany N.} and Slav{\'e} Petrovski and Sapp, {Peter C.} and Dion, {Patrick A.} and Leblond, {Claire S.} and Julien Couthouis and Lu, {Yi Fan} and Quanli Wang and Krueger, {Brian J.} and Zhong Ren and Jonathan Keebler and Yujun Han and Levy, {Shawn E.} and Boone, {Braden E.} and Wimbish, {Jack R.} and Waite, {Lindsay L.} and Jones, {Angela L.} and Carulli, {John P.} and Day-Williams, {Aaron G.} and Staropoli, {John F.} and Xin, {Winnie W.} and Alessandra Chesi and Raphael, {Alya R.} and Diane McKenna-Yasek and Janet Cady and {De Jong}, {J. M B Vianney} and Kenna, {Kevin P.} and Smith, {Bradley N.} and Simon Topp and Jack Miller and Athina Gkazi and Ammar Al-Chalabi and {Van Den Berg}, {Leonard H.} and Jan Veldink and Vincenzo Silani and Nicola Ticozzi and Shaw, {Christopher E.} and Baloh, {Robert H.} and Stanley Appel and Ericka Simpson and Clotilde Lagier-Tourenne and Pulst, {Stefan M.} and Summer Gibson and Trojanowski, {John Q.} and Lauren Elman and Leo McCluskey and Murray Grossman and Shneider, {Neil A.} and Chung, {Wendy K.} and Ravits, {John M.} and Glass, {Jonathan D.} and Sims, {Katherine B.} and {Van Deerlin}, {Vivianna M.} and Tom Maniatis and Hayes, {Sebastian D.} and Alban Ordureau and Sharan Swarup and John Landers and Frank Baas and Allen, {Andrew S.} and Bedlack, {Richard S.} and Harper, {J. Wade} and Gitler, {Aaron D.} and Rouleau, {Guy A.} and Robert Brown and Harms, {Matthew B.} and Cooper, {Gregory M.} and Tim Harris and Myers, {Richard M.} and Goldstein, {David B.}",

year = "2015",

month = mar,

day = "27",

doi = "10.1126/science.aaa3650",

language = "English",

volume = "347",

pages = "1436--1441",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6229",

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TY - JOUR

T1 - Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

AU - Cirulli, Elizabeth T.

AU - Lasseigne, Brittany N.

AU - Petrovski, Slavé

AU - Sapp, Peter C.

AU - Dion, Patrick A.

AU - Leblond, Claire S.

AU - Couthouis, Julien

AU - Lu, Yi Fan

AU - Wang, Quanli

AU - Krueger, Brian J.

AU - Ren, Zhong

AU - Keebler, Jonathan

AU - Han, Yujun

AU - Levy, Shawn E.

AU - Boone, Braden E.

AU - Wimbish, Jack R.

AU - Waite, Lindsay L.

AU - Jones, Angela L.

AU - Carulli, John P.

AU - Day-Williams, Aaron G.

AU - Staropoli, John F.

AU - Xin, Winnie W.

AU - Chesi, Alessandra

AU - Raphael, Alya R.

AU - McKenna-Yasek, Diane

AU - Cady, Janet

AU - De Jong, J. M B Vianney

AU - Kenna, Kevin P.

AU - Smith, Bradley N.

AU - Topp, Simon

AU - Miller, Jack

AU - Gkazi, Athina

AU - Al-Chalabi, Ammar

AU - Van Den Berg, Leonard H.

AU - Veldink, Jan

AU - Silani, Vincenzo

AU - Ticozzi, Nicola

AU - Shaw, Christopher E.

AU - Baloh, Robert H.

AU - Appel, Stanley

AU - Simpson, Ericka

AU - Lagier-Tourenne, Clotilde

AU - Pulst, Stefan M.

AU - Gibson, Summer

AU - Trojanowski, John Q.

AU - Elman, Lauren

AU - McCluskey, Leo

AU - Grossman, Murray

AU - Shneider, Neil A.

AU - Chung, Wendy K.

AU - Ravits, John M.

AU - Glass, Jonathan D.

AU - Sims, Katherine B.

AU - Van Deerlin, Vivianna M.

AU - Maniatis, Tom

AU - Hayes, Sebastian D.

AU - Ordureau, Alban

AU - Swarup, Sharan

AU - Landers, John

AU - Baas, Frank

AU - Allen, Andrew S.

AU - Bedlack, Richard S.

AU - Harper, J. Wade

AU - Gitler, Aaron D.

AU - Rouleau, Guy A.

AU - Brown, Robert

AU - Harms, Matthew B.

AU - Cooper, Gregory M.

AU - Harris, Tim

AU - Myers, Richard M.

AU - Goldstein, David B.

PY - 2015/3/27

Y1 - 2015/3/27

N2 - Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment.We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment.We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

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DO - 10.1126/science.aaa3650

M3 - Article

C2 - 25700176

AN - SCOPUS:84945749129

SN - 0036-8075

VL - 347

SP - 1436

EP - 1441

JO - Science

JF - Science

IS - 6229

ER -

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

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