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; FALS Sequencing Consortium

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, FALS Sequencing Consortium

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

848 Scopus citations

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 (US)
Pages (from-to)	1436-41
Number of pages	6
Journal	Science (New York, N.Y.)
Volume	347
Issue number	6229
DOIs	https://doi.org/10.1126/science.aaa3650
State	Published - Mar 27 2015

Keywords

Adaptor Proteins, Signal Transducing
Adolescent
Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis
Autophagy
Exome
Female
Genes
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Protein Binding
Protein-Serine-Threonine Kinases
Risk
Sequence Analysis, DNA
Transcription Factor TFIIIA
Young Adult

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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., ... FALS Sequencing Consortium (2015). Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science (New York, N.Y.), 347(6229), 1436-41. https://doi.org/10.1126/science.aaa3650

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 & FALS Sequencing Consortium 2015, 'Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways', Science (New York, N.Y.), vol. 347, no. 6229, pp. 1436-41. https://doi.org/10.1126/science.aaa3650

@article{26a257a8c93549f8a18c2528e641419d,

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.",

keywords = "Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Autophagy, Exome, Female, Genes, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Protein Binding, Protein-Serine-Threonine Kinases, Risk, Sequence Analysis, DNA, Transcription Factor TFIIIA, Young Adult",

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 Yi-Fan Lu 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 \{Vianney de Jong\}, \{J M B\} 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 \{FALS Sequencing Consortium\}",

note = "Copyright {\textcopyright} 2015, American Association for the Advancement of Science.",

year = "2015",

month = mar,

day = "27",

doi = "10.1126/science.aaa3650",

language = "English (US)",

volume = "347",

pages = "1436--41",

journal = "Science (New York, N.Y.)",

issn = "0036-8075",

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

number = "6229",

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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 - Vianney de Jong, J M B

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 - FALS Sequencing Consortium

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.

KW - Adaptor Proteins, Signal Transducing

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Amyotrophic Lateral Sclerosis

KW - Autophagy

KW - Exome

KW - Female

KW - Genes

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Humans

KW - Male

KW - Middle Aged

KW - Protein Binding

KW - Protein-Serine-Threonine Kinases

KW - Risk

KW - Sequence Analysis, DNA

KW - Transcription Factor TFIIIA

KW - Young Adult

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UR - https://www.scopus.com/inward/citedby.url?scp=84945749129&partnerID=8YFLogxK

U2 - 10.1126/science.aaa3650

DO - 10.1126/science.aaa3650

M3 - Article

C2 - 25700176

SN - 0036-8075

VL - 347

SP - 1436

EP - 1441

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6229

ER -

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Abstract

Keywords

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