Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

被引:727
作者
Cirulli, Elizabeth T. [1 ]
Lasseigne, Brittany N. [2 ]
Petrovski, Slave [3 ]
Sapp, Peter C. [4 ]
Dion, Patrick A. [5 ]
Leblond, Claire S. [5 ]
Couthouis, Julien [6 ]
Lu, Yi-Fan [3 ]
Wang, Quanli [3 ]
Krueger, Brian J. [3 ]
Ren, Zhong [3 ]
Keebler, Jonathan [7 ]
Han, Yujun [7 ]
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, Alessandra [6 ]
Raphael, Alya R. [6 ]
McKenna-Yasek, Diane [4 ]
Cady, Janet [10 ]
de Jong, J. M. B. Vianney [11 ]
Kenna, Kevin P. [12 ]
Smith, Bradley N. [13 ]
Topp, Simon [13 ]
Miller, Jack [13 ]
Gkazi, Athina [13 ]
Al-Chalabi, Ammar [13 ]
van den Berg, Leonard H. [14 ]
Veldink, Jan [14 ]
Silani, Vincenzo [15 ,16 ,17 ]
Ticozzi, Nicola [15 ,16 ,17 ]
Shaw, Christopher E. [13 ]
Baloh, Robert H. [18 ]
Appel, Stanley [19 ,20 ]
Simpson, Ericka [19 ,20 ]
lagier-Tourenne, ClotilDe [21 ,22 ]
Pulst, Stefan M. [23 ]
Gibson, Summer [23 ]
Trojanowski, John Q. [24 ]
Elman, Lauren [25 ]
McCluskey, Leo [25 ]
Grossman, Murray [26 ]
Shneider, Neil A. [27 ]
Chung, Wendy K. [28 ]
机构
[1] Duke Univ, Sch Med, Ctr Appl Genom & Precis Med, Durham, NC 27708 USA
[2] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA
[3] Columbia Univ, Inst Genom Med, New York, NY 10032 USA
[4] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA
[5] McGill Univ, Dept Neurol & Neurosurg, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada
[6] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA
[7] Duke Univ, Sch Med, Durham, NC 27708 USA
[8] Biogen Inc, Cambridge, MA 02142 USA
[9] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Neurogenet DNA Diagnost Lab, Boston, MA 02114 USA
[10] Washington Univ, Sch Med, Neurol, St Louis, MO 63110 USA
[11] Univ Amsterdam, Acad Med Ctr, Dept Genome Anal, NL-1105 AZ Amsterdam, Netherlands
[12] Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Acad Unit Neurol, Dublin, Ireland
[13] Kings Coll London, Dept Basic & Clin Neurosci, Inst Psychiat, London SE5 8AF, England
[14] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, NL-3508 GA Utrecht, Netherlands
[15] IRCCS Ist Auxol ltaliano, Dept Neurol, I-20149 Milan, Italy
[16] IRCCS Ist Auxol ltaliano, Lab Neurosci, I-20149 Milan, Italy
[17] Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, I-20122 Milan, Italy
[18] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA
[19] Houston Methodist Hosp, Houston, TX 77030 USA
[20] Cornell Univ, Weill Cornell Med Coll, New York, NY 10065 USA
[21] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA
[22] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[23] Univ Utah, Sch Med, Dept Neurol, Salt Lake City, UT 84112 USA
[24] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[25] Univ Penn, Perelman Sch Med, Penn ALS Ctr, Dept Neurol, Philadelphia, PA 19104 USA
[26] Univ Penn, Perelman Sch Med, Penn Frontotemporal Degenerat Ctr, Dept Neurol, Philadelphia, PA 19104 USA
[27] Columbia Univ, Ctr Motor Neuron Biol & Dis, Dept Neurol, New York, NY 10032 USA
[28] Columbia Univ, Dept Pediat & Med, New York, NY 10032 USA
[29] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA
[30] Columbia Univ, Dept Biochem Mol Biophys, New York, NY 10027 USA
[31] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[32] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC 27708 USA
[33] Duke ALS Clin, Durham, NC 27708 USA
[34] Durham VA Med Ctr, Durham, NC 27708 USA
基金
美国国家科学基金会;
关键词
AUTOPHAGY RECEPTOR; SPASTIN GENE; D-SERINE; OPTINEURIN; MUTATIONS; ALS; GRANULES; BINDING; PROTEIN; ROLES;
D O I
10.1126/science.aaa3650
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:1436 / 1441
页数:6
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