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.
authors.affiliation: Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC 27708, USA.
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Cirulli
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Lasseigne
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Slavé
authors.initials: S
authors.lastname: Petrovski
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Sapp
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leblond
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Couthouis
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lu
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Quanli
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Krueger
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Duke University School of Medicine, Durham, NC 27708, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Keebler
authors.affiliation: Duke University School of Medicine, Durham, NC 27708, USA.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Han
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Levy
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Braden E
authors.initials: BE
authors.lastname: Boone
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wimbish
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Lindsay L
authors.initials: LL
authors.lastname: Waite
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Jones
authors.affiliation: Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Carulli
authors.affiliation: Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Day-Williams
authors.affiliation: Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: John F
authors.initials: JF
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authors.affiliation: Neurogenetics DNA Diagnostic Laboratory, Center for Human Genetics Research, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
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authors.initials: WW
authors.lastname: Xin
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Chesi
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Alya R
authors.initials: AR
authors.lastname: Raphael
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
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authors.initials: D
authors.lastname: McKenna-Yasek
authors.affiliation: Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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authors.affiliation: Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, Netherlands.
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authors.initials: JM
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authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.
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authors.initials: KP
authors.lastname: Kenna
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.
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authors.initials: BN
authors.lastname: Smith
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Topp
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.
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authors.initials: J
authors.lastname: Miller
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.
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authors.initials: A
authors.lastname: Gkazi
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, 3508 GA Utrecht, Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, 3508 GA Utrecht, Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Veldink
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy, and Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan 20122, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy, and Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan 20122, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ticozzi
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.
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authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
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authors.initials: RH
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authors.affiliation: Houston Methodist Hospital, Houston, TX 77030, USA, and Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
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authors.initials: S
authors.lastname: Appel
authors.affiliation: Houston Methodist Hospital, Houston, TX 77030, USA, and Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
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authors.initials: E
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authors.affiliation: Ludwig Institute for Cancer Research and Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.affiliation: Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
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authors.initials: SM
authors.lastname: Pulst
authors.affiliation: Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Summer
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authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Neurology, Penn ALS Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.initials: L
authors.lastname: Elman
authors.affiliation: Department of Neurology, Penn ALS Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.initials: L
authors.lastname: McCluskey
authors.affiliation: Department of Neurology, Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.affiliation: Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
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authors.initials: NA
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authors.affiliation: Department of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
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authors.initials: WK
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authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
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authors.initials: JM
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authors.affiliation: Department of Neurology, Emory University, Atlanta, GA 30322, USA.
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authors.affiliation: Neurogenetics DNA Diagnostic Laboratory, Center for Human Genetics Research, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
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authors.initials: KB
authors.lastname: Sims
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.initials: VM
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authors.affiliation: Department of Biochemistry & Molecular Biophysics, Columbia University, New York, NY 10027, USA.
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authors.lastname: Maniatis
authors.affiliation: Biogen Idec, Cambridge, MA 02142, USA. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
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authors.initials: SD
authors.lastname: Hayes
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
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authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
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authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
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authors.affiliation: Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, Netherlands.
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authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27708, USA.
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authors.initials: RS
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authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
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authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.affiliation: Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cooper
authors.affiliation: Biogen Idec, Cambridge, MA 02142, USA. tim.harris@biogenidec.com.
authors.forename: Tim
authors.initials: T
authors.lastname: Harris
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: David B
authors.initials: DB
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mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics*; D018797:Cell Cycle Proteins; D059472:Exome / Q000235:genetics*; D005260:Female; D005796:Genes; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012306:Risk; D017422:Sequence Analysis, DNA; D000071456:Sequestosome-1 Protein; D035582:Transcription Factor TFIIIA / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D035582:Transcription Factor TFIIIA; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human