Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes

TY - JOUR

T1 - Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes

AU - Jones, Ashley R

AU - Troakes, Claire

AU - King, Andrew

AU - Sahni, Vibhu

AU - De Jong, Simone

AU - Bossers, Koen

AU - Papouli, Efterpi

AU - Mirza, Muddassar

AU - Al-Sarraj, Safa

AU - Shaw, Christopher E

AU - Shaw, Pamela J

AU - Kirby, Janine

AU - Veldink, Jan H

AU - Macklis, Jeffrey D

AU - Powell, John F

AU - Al-Chalabi, Ammar

PY - 2015/2/19

Y1 - 2015/2/19

N2 - 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.

AB - 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.

U2 - 10.1016/j.neurobiolaging.2015.02.017

DO - 10.1016/j.neurobiolaging.2015.02.017

M3 - Article

C2 - 25801576

SN - 0197-4580

SP - 2006.e1-2006.e9

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -