title: Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes.
abstract: 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 × 10(-5)). Analyses stratified by disease severity identified expression changes in C9orf72 (p = 2.77 × 10(-3)), MATR3 (p = 3.46 × 10(-3)), and VEGFA (p = 8.21 × 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.
authors: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors: Ashley R
authors: AR
authors: Jones
authors: MRC London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
authors: Claire
authors: C
authors: Troakes
authors: MRC London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
authors: Andrew
authors: A
authors: King
authors: Department of Stem Cell and Regenerative Biology, Center for Brain Science, Harvard University, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
authors: Vibhu
authors: V
authors: Sahni
authors: MRC Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors: Simone
authors: S
authors: De Jong
authors: Synaptic Plasticity and Behavior Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
authors: Koen
authors: K
authors: Bossers
authors: Biomedical Research Centre, King's College London, Guy's Hospital, London, UK; Cambridge Epigenetix Ltd, Babraham, UK.
authors: Efterpi
authors: E
authors: Papouli
authors: Biomedical Research Centre, King's College London, Guy's Hospital, London, UK.
authors: Muddassar
authors: M
authors: Mirza
authors: MRC London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
authors: Safa
authors: S
authors: Al-Sarraj
authors: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors: Christopher E
authors: CE
authors: Shaw
authors: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors: Pamela J
authors: PJ
authors: Shaw
authors: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors: Janine
authors: J
authors: Kirby
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Jan H
authors: JH
authors: Veldink
authors: Department of Stem Cell and Regenerative Biology, Center for Brain Science, Harvard University, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
authors: Jeffrey D
authors: JD
authors: Macklis
authors: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors: John F
authors: JF
authors: Powell
authors: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address: ammar.al-chalabi@kcl.ac.uk.
authors: Ammar
authors: A
authors: Al-Chalabi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D006801:Humans; D007109:Immunity / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C518587:MATR3 protein, human; D034521:Nuclear Matrix-Associated Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Amyotrophic lateral sclerosis; C9ORF72; Disease spread; Gene expression; RNA processing; Spinal cord