Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

被引：741

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

来源：

SCIENCE | 2015年 / 347卷 / 6229期

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

页码：1436 / 1441

页数：6

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