Genomic biomarkers and genetic risk factors in amyotrophic lateral sclerosis

Abstract

In this thesis, we focus our biomarker discovery on gene expression in blood of an ALS mouse model and ALS patients to find ALS specific gene activity. 1. To explore the potential of blood or muscle transcriptome changes as a diagnostic biomarker. We hypothesized that blood gene expression reflects gene expression in the brain and in motor neurons. We used an SOD1 mouse model overexpressing human mutant SOD1-G93A to compare differentially expressed genes in spinal cord with differential expression in blood and muscle (Chapter 3). Next we analyzed gene expression in blood of sporadic ALS patients and healthy controls and constructed groups of co-differentially, co-expressed genes (Chapter 5). From the finding of altered gene activity in ALS patients, we profiled a larger dataset and constructed a panel that can discriminate with high accuracy between ALS patients and healthy controls (Chapter 6). 2. To find genetic variation associated with ALS and controlling gene expression in blood of ALS patients We performed a two-stage, genome-wide association study (GWAS) to find genetic risk factors associated with ALS (Chapter 7). Combining the gene expression data with genetic variation of sporadic ALS patients made it possible to select genetic variation causing differences in quantitative levels of expression (Chapter 8). This genetical genomics exercise can fine-map previously found linked loci and has the potential of finding new genetic risk factors. 3. To find the underlying pathological pathways in ALS mouse models. The exact pathological mechanism causing motor neuron degeneration is still elusive. We performed a meta-analysis of all published studies using gene expression in ALS mouse models (Chapter 2). Overlap in differential expression might provide important information on common pathological pathways. Next we determined differential gene expression in spinal cord of an SOD1 mouse model as part of our biomarker study (Chapter 3). 4. To find pathways targeted by riluzole. Since riluzole is the only effective drug in ALS, elucidating the mechanism of efficacy of this drug will immediately be relevant to the etiology of this disease. Gene expression profiles of SOD1-G93A mice treated with riluzole were compared to control animals receiving only tap water (Chapter 4). Expression profiles were determined in lumbar spinal cord at pre-symptomatic and early symptomatic ages.