Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

doi:10.1126/science.aaa3650

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

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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)	1436-41
Number of pages	6
Journal	Science
Volume	347
Issue number	6229
DOIs	https://doi.org/10.1126/science.aaa3650
Publication status	Published - 27 Mar 2015

Keywords

Adaptor Proteins, Signal Transducing/genetics
Adolescent
Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis/genetics
Autophagy/genetics
Cell Cycle Proteins
Exome/genetics
Female
Genes
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Male
Membrane Transport Proteins
Middle Aged
Protein Binding
Protein-Serine-Threonine Kinases/genetics
Risk
Sequence Analysis, DNA
Sequestosome-1 Protein
Transcription Factor TFIIIA/genetics
Young Adult

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@article{2b48243c88b54abca69a8e0a982587ce,

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/genetics, Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis/genetics, Autophagy/genetics, Cell Cycle Proteins, Exome/genetics, Female, Genes, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Membrane Transport Proteins, Middle Aged, Protein Binding, Protein-Serine-Threonine Kinases/genetics, Risk, Sequence Analysis, DNA, Sequestosome-1 Protein, Transcription Factor TFIIIA/genetics, 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}",

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

year = "2015",

month = mar,

day = "27",

doi = "10.1126/science.aaa3650",

language = "English",

volume = "347",

pages = "1436--41",

journal = "Science",

issn = "0036-8075",

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

number = "6229",

}

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 - 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

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/genetics

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Amyotrophic Lateral Sclerosis/genetics

KW - Autophagy/genetics

KW - Cell Cycle Proteins

KW - Exome/genetics

KW - Female

KW - Genes

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Humans

KW - Male

KW - Membrane Transport Proteins

KW - Middle Aged

KW - Protein Binding

KW - Protein-Serine-Threonine Kinases/genetics

KW - Risk

KW - Sequence Analysis, DNA

KW - Sequestosome-1 Protein

KW - Transcription Factor TFIIIA/genetics

KW - Young Adult

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

JF - Science

IS - 6229

ER -

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Abstract

Keywords

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