Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Author:

Cirulli Elizabeth T.1,Lasseigne Brittany N.2,Petrovski Slavé3,Sapp Peter C.4,Dion Patrick A.5,Leblond Claire S.5,Couthouis Julien6,Lu Yi-Fan3,Wang Quanli3,Krueger Brian J.3,Ren Zhong3,Keebler Jonathan7,Han Yujun7,Levy Shawn E.2,Boone Braden E.2,Wimbish Jack R.2,Waite Lindsay L.2,Jones Angela L.2,Carulli John P.8,Day-Williams Aaron G.8,Staropoli John F.8,Xin Winnie W.9,Chesi Alessandra6,Raphael Alya R.6,McKenna-Yasek Diane4,Cady Janet10,Vianney de Jong J. M. B.11,Kenna Kevin P.12,Smith Bradley N.13,Topp Simon13,Miller Jack13,Gkazi Athina13,Al-Chalabi Ammar13,van den Berg Leonard H.14,Veldink Jan14,Silani Vincenzo15,Ticozzi Nicola15,Shaw Christopher E.13,Baloh Robert H.16,Appel Stanley17,Simpson Ericka17,Lagier-Tourenne Clotilde18,Pulst Stefan M.19,Gibson Summer19,Trojanowski John Q.20,Elman Lauren21,McCluskey Leo21,Grossman Murray22,Shneider Neil A.23,Chung Wendy K.24,Ravits John M.25,Glass Jonathan D.26,Sims Katherine B.9,Van Deerlin Vivianna M.20,Maniatis Tom27,Hayes Sebastian D.828,Ordureau Alban28,Swarup Sharan28,Landers John4,Baas Frank11,Allen Andrew S.29,Bedlack Richard S.30,Harper J. Wade28,Gitler Aaron D.6,Rouleau Guy A.5,Brown Robert4,Harms Matthew B.10,Cooper Gregory M.2,Harris Tim8,Myers Richard M.2,Goldstein David B.3,

Affiliation:

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. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

29. Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27708, USA.

30. Duke ALS Clinic and Durham VA Medical Center, Durham, NC 27708, USA.

Abstract

New players in Lou Gehrig's disease Amyotrophic lateral sclerosis (ALS), often referred to as “Lou Gehrig's disease,” is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Cirulli et al. sequenced the expressed genes of nearly 3000 ALS patients and compared them with those of more than 6000 controls (see the Perspective by Singleton and Traynor). They identified several proteins that were linked to disease in patients. One such protein, TBK1, is implicated in innate immunity and autophagy and may represent a therapeutic target. Science , this issue p. 1436 ; see also p. 1422

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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