Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

E.T. Cirulli; B.N. Lasseigne; S. Petrovski; P.C. Sapp; P.A. Dion; C.S. Leblond; J. Couthouis; Y.-F. Lu; Q. Wang; B.J. Krueger; Z. Ren; J. Keebler; Y. Han; S.E. Levy; B.E. Boone; J.R. Wimbish; L.L. Waite; A.L. Jones; J.P. Carulli; A.G. Day-Williams; J.F. Staropoli; W.W. Xin; A. Chesi; A.R. Raphael; D. McKenna-Yasek; J. Cady; J. M. B. Vianney de Jong; K. P. Kenna; B. N. Smith; S. Topp; J. Miller; A. Gkazi; A. Al-Chalabi; L.H. van den Berg; J. Veldink; V. Silani; N. Ticozzi; C. E. Shaw; R. H. Baloh; S. Appel; E. Simpson; C. Lagier-Tourenne; S.M. Pulst; S. Gibson; J. Q. Trojanowski; L. Elman; L. McCluskey; M. Grossman; N.A. Shneider; W. K. Chung; J. M. Ravits; J. D. Glass; K. B. Sims; V.M. Van Deerlin; T. Maniatis; S.D. Hayes; A. Ordureau; S. Swarup; J. Landers; F. Baas; A.S. Allen; R.S. Bedlack; J.W. Harper; A.D. Gitler; G. A. Rouleau; R. Brown; M.B. Harms; G.M. Cooper; T. Harris; R.M. Myers; D.B. Goldstein; K.E. Morrison

doi:10.1126/science.aaa3650

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

E.T. Cirulli
, B.N. Lasseigne
, S. Petrovski
, P.C. Sapp
, P.A. Dion
, C.S. Leblond
, J. Couthouis
, Y.-F. Lu
, Q. Wang
, B.J. Krueger
, Z. Ren
, J. Keebler
, Y. Han
, S.E. Levy
, B.E. Boone
, J.R. Wimbish
, L.L. Waite
, A.L. Jones
, J.P. Carulli
, A.G. Day-Williams

J.F. Staropoli, W.W. Xin, A. Chesi, A.R. Raphael, D. McKenna-Yasek, J. Cady, J. M. B. Vianney de Jong, K. P. Kenna, B. N. Smith, S. Topp, J. Miller, A. Gkazi, A. Al-Chalabi, L.H. van den Berg, J. Veldink, V. Silani, N. Ticozzi, C. E. Shaw, R. H. Baloh, S. Appel, E. Simpson, C. Lagier-Tourenne, S.M. Pulst, S. Gibson, J. Q. Trojanowski, L. Elman, L. McCluskey, M. Grossman, N.A. Shneider, W. K. Chung, J. M. Ravits, J. D. Glass, K. B. Sims, V.M. Van Deerlin, T. Maniatis, S.D. Hayes, A. Ordureau, S. Swarup, J. Landers, F. Baas, A.S. Allen, R.S. Bedlack, J.W. Harper, A.D. Gitler, G. A. Rouleau, R. Brown, M.B. Harms, G.M. Cooper, T. Harris, R.M. Myers, D.B. Goldstein, K.E. Morrison

School of Medicine, Dentistry and Biomedical Sciences

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

842 Citations (Scopus)

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
Journal	Science
Volume	347
Issue number	6229
DOIs	https://doi.org/10.1126/science.aaa3650
Publication status	Published - 27 Mar 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., ... Morrison, K. E. (2015). Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science, 347(6229), 1436-1441. https://doi.org/10.1126/science.aaa3650

@article{9936cb5b7db645e3b2f72997ce813ffb,

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 = "E.T. Cirulli and B.N. Lasseigne and S. Petrovski and P.C. Sapp and P.A. Dion and C.S. Leblond and J. Couthouis and Y.-F. Lu and Q. Wang and B.J. Krueger and Z. Ren and J. Keebler and Y. Han and S.E. Levy and B.E. Boone and J.R. Wimbish and L.L. Waite and A.L. Jones and J.P. Carulli and A.G. Day-Williams and J.F. Staropoli and W.W. Xin and A. Chesi and A.R. Raphael and D. McKenna-Yasek and J. Cady and \{Vianney de Jong\}, \{J. M. B.\} and Kenna, \{K. P.\} and Smith, \{B. N.\} and S. Topp and J. Miller and A. Gkazi and A. Al-Chalabi and \{van den Berg\}, L.H. and J. Veldink and V. Silani and N. Ticozzi and Shaw, \{C. E.\} and Baloh, \{R. H.\} and S. Appel and E. Simpson and C. Lagier-Tourenne and S.M. Pulst and S. Gibson and Trojanowski, \{J. Q.\} and L. Elman and L. McCluskey and M. Grossman and N.A. Shneider and Chung, \{W. K.\} and Ravits, \{J. M.\} and Glass, \{J. D.\} and Sims, \{K. B.\} and \{Van Deerlin\}, V.M. and T. Maniatis and S.D. Hayes and A. Ordureau and S. Swarup and J. Landers and F. Baas and A.S. Allen and R.S. Bedlack and J.W. Harper and A.D. Gitler and Rouleau, \{G. A.\} and R. Brown and M.B. Harms and G.M. Cooper and T. Harris and R.M. Myers and D.B. Goldstein and K.E. Morrison",

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",

}

Cirulli, ET, Lasseigne, BN, Petrovski, S, Sapp, PC, Dion, PA, Leblond, CS, Couthouis, J, Lu, Y-F, 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, Vianney de Jong, JMB, 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 & Morrison, KE 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

TY - JOUR

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

AU - Cirulli, E.T.

AU - Lasseigne, B.N.

AU - Petrovski, S.

AU - Sapp, P.C.

AU - Dion, P.A.

AU - Leblond, C.S.

AU - Couthouis, J.

AU - Lu, Y.-F.

AU - Wang, Q.

AU - Krueger, B.J.

AU - Ren, Z.

AU - Keebler, J.

AU - Han, Y.

AU - Levy, S.E.

AU - Boone, B.E.

AU - Wimbish, J.R.

AU - Waite, L.L.

AU - Jones, A.L.

AU - Carulli, J.P.

AU - Day-Williams, A.G.

AU - Staropoli, J.F.

AU - Xin, W.W.

AU - Chesi, A.

AU - Raphael, A.R.

AU - McKenna-Yasek, D.

AU - Cady, J.

AU - Vianney de Jong, J. M. B.

AU - Kenna, K. P.

AU - Smith, B. N.

AU - Topp, S.

AU - Miller, J.

AU - Gkazi, A.

AU - Al-Chalabi, A.

AU - van den Berg, L.H.

AU - Veldink, J.

AU - Silani, V.

AU - Ticozzi, N.

AU - Shaw, C. E.

AU - Baloh, R. H.

AU - Appel, S.

AU - Simpson, E.

AU - Lagier-Tourenne, C.

AU - Pulst, S.M.

AU - Gibson, S.

AU - Trojanowski, J. Q.

AU - Elman, L.

AU - McCluskey, L.

AU - Grossman, M.

AU - Shneider, N.A.

AU - Chung, W. K.

AU - Ravits, J. M.

AU - Glass, J. D.

AU - Sims, K. B.

AU - Van Deerlin, V.M.

AU - Maniatis, T.

AU - Hayes, S.D.

AU - Ordureau, A.

AU - Swarup, S.

AU - Landers, J.

AU - Baas, F.

AU - Allen, A.S.

AU - Bedlack, R.S.

AU - Harper, J.W.

AU - Gitler, A.D.

AU - Rouleau, G. A.

AU - Brown, R.

AU - Harms, M.B.

AU - Cooper, G.M.

AU - Harris, T.

AU - Myers, R.M.

AU - Goldstein, D.B.

AU - Morrison, K.E.

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.

U2 - 10.1126/science.aaa3650

DO - 10.1126/science.aaa3650

M3 - Article

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

Abstract

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