Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes

NEUROBIOLOGY OF AGING

卷:36

Article

Jones, Ashley R.¹  Troakes, Claire²  King, Andrew²  Sahni, Vibhu^3,4  De Jong, Simone⁵  Bossers, Koen⁶  Papouli, Efterpi^7,8  Mirza, Muddassar⁷  Al-Sarraj, Safa²  Shaw, Pamela J.⁹  Kirby, Janine⁹  Veldink, Jan H.¹⁰  Macklis, Jeffrey D.^3,4  Powell, John F.¹  Al-Chalabi, Ammar¹ 

[1] Kings Coll London, Dept Basic & Clin Neurosci, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England

[2] Kings Coll London, MRC London Neurodegenerat Dis Brain Bank, London SE5 8AF, England

[3] Harvard Univ, Dept Stem Cell & Regenerat Biol, Ctr Brain Sci, Cambridge, MA 02138 USA

[4] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[5] Kings Coll London, MRC Social Genet & Dev Psychiat Res Ctr, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England

[6] Netherlands Inst Neurosci, Synapt Plast & Behav Grp, Amsterdam, Netherlands

[7] Kings Coll London, Guys Hosp, Biomed Res Ctr, London SE5 8AF, England

[8] Cambridge Epigenetix Ltd, Babraham, England

[9] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Sheffield, S Yorkshire, England

[10] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands

关键词: Gene expression;    Amyotrophic lateral sclerosis;    Spinal cord;    Disease spread;    C9ORF72;    RNA processing;   

DOI  :  10.1016/j.neurobiolaging.2015.02.017

来源: Elsevier

【 摘 要 】

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis. Gene expression studies of ALS only rarely identify the same gene pathways as gene association studies. We hypothesized that analyzing tissues by matching on degree of disease severity would identify different patterns of gene expression from a traditional case-control comparison. We analyzed gene expression changes in 4 postmortem central nervous system regions, stratified by severity of motor neuron loss. An overall comparison of cases (n = 6) and controls (n = 3) identified known ALS gene, SOX5, as showing differential expression (log2 fold change = 0.09, p = 5.5 x 10(-5)). Analyses stratified by disease severity identified expression changes in C9orf72 (p = 2.77 x 10(-3)), MATR3 (p = 3.46 x 10(-3)), and VEGFA (p = 8.21 x 10(-4)), all implicated in ALS through genetic studies, and changes in other genes in pathways involving RNA processing and immune response. These findings suggest that analysis of gene expression stratified by disease severity can identify major ALS genes and may be more efficient than traditional case-control comparison. (C) 2015 Elsevier Inc. All rights reserved.

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