. 2015 Mar 27;347(6229):1436-41.

doi: 10.1126/science.aaa3650. Epub 2015 Feb 19.

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Elizabeth T Cirulli¹, Brittany N Lasseigne², Slavé Petrovski³, Peter C Sapp⁴, Patrick A Dion⁵, Claire S Leblond⁵, Julien Couthouis⁶, Yi-Fan Lu³, Quanli Wang³, Brian J Krueger³, Zhong Ren³, Jonathan Keebler⁷, Yujun Han⁷, Shawn E Levy², Braden E Boone², Jack R Wimbish², Lindsay L Waite², Angela L Jones², John P Carulli⁸, Aaron G Day-Williams⁸, John F Staropoli⁸, Winnie W Xin⁹, Alessandra Chesi⁶, Alya R Raphael⁶, Diane McKenna-Yasek⁴, Janet Cady¹⁰, J M B Vianney de Jong¹¹, Kevin P Kenna¹², Bradley N Smith¹³, Simon Topp¹³, Jack Miller¹³, Athina Gkazi¹³; FALS Sequencing Consortium; Ammar Al-Chalabi¹³, Leonard H van den Berg¹⁴, Jan Veldink¹⁴, Vincenzo Silani¹⁵, Nicola Ticozzi¹⁵, Christopher E Shaw¹³, Robert H Baloh¹⁶, Stanley Appel¹⁷, Ericka Simpson¹⁷, Clotilde Lagier-Tourenne¹⁸, Stefan M Pulst¹⁹, Summer Gibson¹⁹, John Q Trojanowski²⁰, Lauren Elman²¹, Leo McCluskey²¹, Murray Grossman²², Neil A Shneider²³, Wendy K Chung²⁴, John M Ravits²⁵, Jonathan D Glass²⁶, Katherine B Sims⁹, Vivianna M Van Deerlin²⁰, Tom Maniatis²⁷, Sebastian D Hayes²⁸, Alban Ordureau²⁹, Sharan Swarup²⁹, John Landers⁴, Frank Baas¹¹, Andrew S Allen³⁰, Richard S Bedlack³¹, J Wade Harper²⁹, Aaron D Gitler⁶, Guy A Rouleau⁵, Robert Brown⁴, Matthew B Harms¹⁰, Gregory M Cooper², Tim Harris³², Richard M Myers², David B Goldstein³

Collaborators, Affiliations

Collaborators

FALS Sequencing Consortium:
Peter C Sapp, Claire S Leblond, Diane McKenna-Yasek, 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, John Landers, Frank Baas, Christopher E Shaw, Jonathan D Glass, Guy A Rouleau, Robert Brown, Orla Hardiman, Russell L McLaughlin, Letizia Mazzini, Ian P Blair, Kelly L Williams, Garth A Nicholson, Safa Al-Sarraj, Andrew King, Emma L Scotter, Simon Topp, Claire Troakes, Caroline Vance, Sandra D'Alfonso, Stefano Duga, Lucia Corrado, Anneloor L M A ten Asbroek, Daniela Calini, Claudia Colombrita, Antonia Ratti, Cinzia Tiloca, Zheyang Wu, Seneshaw Asress, Meraida Polak, Frank Diekstra, Wouter van Rheenen, Eric W Danielson, Claudia Fallini, Pamela Keagle, Elizabeth A Lewis, Jason Kost, Gianni Sorarù, Cinzia Bertolin, Giorgia Querin, Barbara Castellotti, Cinzia Gellera, Viviana Pensato, Franco Taroni, Cristina Cereda, Stella Gagliardi, Mauro Ceroni, Giuseppe Lauria, Jacqueline de Belleroche, Giacomo P Comi, Stefania Corti, Roberto Del Bo, Martin R Turner, Kevin Talbot, Hardev Pall, Karen E Morrison, Pamela J Shaw, Jesús Esteban-Pérez, Alberto García-Redondo, José Luis Muñoz-Blanco

Affiliations

¹ Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC 27708, USA.
² HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
³ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
⁴ Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
⁵ Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Duke University School of Medicine, Durham, NC 27708, USA.
⁸ Biogen Idec, Cambridge, MA 02142, USA.
⁹ Neurogenetics DNA Diagnostic Laboratory, Center for Human Genetics Research, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹¹ Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, Netherlands.
¹² Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.
¹³ Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.
¹⁴ Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, 3508 GA Utrecht, Netherlands.
¹⁵ 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.
¹⁶ Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁷ Houston Methodist Hospital, Houston, TX 77030, USA, and Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
¹⁸ Ludwig Institute for Cancer Research and Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁹ Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
²⁰ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
²¹ Department of Neurology, Penn ALS Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
²² Department of Neurology, Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
²³ Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
²⁴ Department of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
²⁵ Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
²⁶ Department of Neurology, Emory University, Atlanta, GA 30322, USA.
²⁷ Department of Biochemistry & Molecular Biophysics, Columbia University, New York, NY 10027, USA.
²⁸ Biogen Idec, Cambridge, MA 02142, USA. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
²⁹ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
³⁰ Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27708, USA.
³¹ Duke ALS Clinic and Durham VA Medical Center, Durham, NC 27708, USA.
³² Biogen Idec, Cambridge, MA 02142, USA. tim.harris@biogenidec.com.

PMID: 25700176
PMCID: PMC4437632
DOI: 10.1126/science.aaa3650

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Elizabeth T Cirulli et al. Science. 2015.

. 2015 Mar 27;347(6229):1436-41.

doi: 10.1126/science.aaa3650. Epub 2015 Feb 19.

Authors

Collaborators

FALS Sequencing Consortium:
Peter C Sapp, Claire S Leblond, Diane McKenna-Yasek, 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, John Landers, Frank Baas, Christopher E Shaw, Jonathan D Glass, Guy A Rouleau, Robert Brown, Orla Hardiman, Russell L McLaughlin, Letizia Mazzini, Ian P Blair, Kelly L Williams, Garth A Nicholson, Safa Al-Sarraj, Andrew King, Emma L Scotter, Simon Topp, Claire Troakes, Caroline Vance, Sandra D'Alfonso, Stefano Duga, Lucia Corrado, Anneloor L M A ten Asbroek, Daniela Calini, Claudia Colombrita, Antonia Ratti, Cinzia Tiloca, Zheyang Wu, Seneshaw Asress, Meraida Polak, Frank Diekstra, Wouter van Rheenen, Eric W Danielson, Claudia Fallini, Pamela Keagle, Elizabeth A Lewis, Jason Kost, Gianni Sorarù, Cinzia Bertolin, Giorgia Querin, Barbara Castellotti, Cinzia Gellera, Viviana Pensato, Franco Taroni, Cristina Cereda, Stella Gagliardi, Mauro Ceroni, Giuseppe Lauria, Jacqueline de Belleroche, Giacomo P Comi, Stefania Corti, Roberto Del Bo, Martin R Turner, Kevin Talbot, Hardev Pall, Karen E Morrison, Pamela J Shaw, Jesús Esteban-Pérez, Alberto García-Redondo, José Luis Muñoz-Blanco

Affiliations

¹ Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC 27708, USA.
² HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
³ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
⁴ Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
⁵ Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Duke University School of Medicine, Durham, NC 27708, USA.
⁸ Biogen Idec, Cambridge, MA 02142, USA.
⁹ Neurogenetics DNA Diagnostic Laboratory, Center for Human Genetics Research, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹¹ Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, Netherlands.
¹² Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.
¹³ Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.
¹⁴ Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, 3508 GA Utrecht, Netherlands.
¹⁵ 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.
¹⁶ Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁷ Houston Methodist Hospital, Houston, TX 77030, USA, and Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
¹⁸ Ludwig Institute for Cancer Research and Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁹ Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
²⁰ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
²¹ Department of Neurology, Penn ALS Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
²² Department of Neurology, Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
²³ Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
²⁴ Department of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
²⁵ Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
²⁶ Department of Neurology, Emory University, Atlanta, GA 30322, USA.
²⁷ Department of Biochemistry & Molecular Biophysics, Columbia University, New York, NY 10027, USA.
²⁸ Biogen Idec, Cambridge, MA 02142, USA. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
²⁹ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
³⁰ Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27708, USA.
³¹ Duke ALS Clinic and Durham VA Medical Center, Durham, NC 27708, USA.
³² Biogen Idec, Cambridge, MA 02142, USA. tim.harris@biogenidec.com.

PMID: 25700176
PMCID: PMC4437632
DOI: 10.1126/science.aaa3650

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.

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Figures

**Fig. 1. QQ plot of discovery results for dominant coding model**
The results for the analysis of 2,874 case and 6,405 control exomes are shown. 16,491 covered genes passed QC with more than one case or control carrier for this test. The genes with the top 10 associations are labeled. The genomic inflation factor, lambda (λ), is 1.061. The association with *SOD1* passed correction for multiple tests.

Fig. 2. Variants in *TARDBP* and *VCP*
Dominant coding variants are shown in *TARDBP* and *VCP* (discovery dataset). Case variants are enriched at the 3′ end of the gene in TARDBP and near the cell division protein 48 domain 2 region in *VCP*. LoF variants are filled in red, non-synonymous variants are filled in blue, and splice variants are filled in purple. Case variants are shown with red lines, control variants are shown with blue lines, and variants found in both cases and controls are shown with dashed lines.

**Fig. 3. A diagram showing the genes and pathways implicated in ALS disease progression**
Genes known to have sequence variants that cause or are associated with ALS are indicated in red. These mutations can lead to the formation of protein, or protein-RNA aggregates that appear as inclusion bodies in postmortem samples from both familial and sporadic ALS patients. Some of the mutant proteins adopt “prion-like” structures (see text for more detail). The misfolded proteins activate the ubiquitin/proteasome autophagy pathways to remove the misfolded proteins. Ubiquilin2 functions in both the Ub-proteosome and autophagy pathways. TBK-1 (boxed) lies at the interface between autophagy and inflammation and associates with and phosphorylates both optineurin and p62, which can, in turn, enhance inflammation. ISG15 is induced by type I interferons (α & β) and interacts with p62 and HDAC6 in the autophagosome.

Fig. 4. Variants in *TBK1* and *OPTN*
Dominant not benign variants are shown in *TBK1* and *OPTN* (combined datasets). LoF variants are filled in red, non-synonymous variants are filled in blue, and splice variants are filled in purple. Case variants are shown with red lines, control variants are shown with blue lines, and variants found in both cases and controls are shown with dashed lines.

See this image and copyright information in PMC

Comment in

Genetics. For complex disease genetics, collaboration drives progress.
Singleton AB, Traynor BJ. Singleton AB, et al. Science. 2015 Mar 27;347(6229):1422-3. doi: 10.1126/science.aaa9838. Science. 2015. PMID: 25814571 Free PMC article. No abstract available.
Something old, something new: TBK1, a novel gene in known amyotrophic lateral sclerosis pathways.
Farhan SM. Farhan SM. Clin Genet. 2015 Oct;88(4):339-40. doi: 10.1111/cge.12624. Epub 2015 Jul 7. Clin Genet. 2015. PMID: 26072952 No abstract available.

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Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Collaborators

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Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Authors

Collaborators

Affiliations

Abstract

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Comment in

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

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