Abstract
Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole-genome expression profiling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed copy number variants (CNVs) occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. A large number of novel and known disease-associated CNVs were detected in SALS samples, including several subgroup-specific loci, suggestive of a great divergence of two subgroups at the molecular level. Integrative analysis of copy number profiles with their associated transcriptomic data revealed subtype-specific genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, suggesting a strong interaction between genomic and transcriptomic events in ALS pathogenesis. The functional analysis confirmed our previous pathway-based characterization of SALS subtypes and identified 24 potential candidates for genomic-based patient stratification. To our knowledge, this is the first comprehensive “omics” analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease.
Highlights
Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease
A total of 488 significant copy number variants (CNVs) ranging in size from 7 bp to 5.9 Mb were identified in sporadic ALS (SALS) patients, including 271 losses and 217 gains (Fig. 1c, Supplementary Table 1)
We reported the first fully integrated analysis of CNVs and gene expression profiling derived from the same SALS patients to provide a more comprehensive genomic framework for dissecting molecular heterogeneity of ALS and identify the differentially expressed genes (DEGs) with alterations in genomic segments that may represent novel potential markers and/or therapeutic targets
Summary
Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. The functional analysis confirmed our previous pathway-based characterization of SALS subtypes and identified 24 potential candidates for genomic-based patient stratification To our knowledge, this is the first comprehensive “omics” analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease. From the discovery of the first ALS-associated gene SOD1, several candidate-gene or genome-wide association studies (GWAS) have identified multiple single-nucleotide polymorphisms (SNPs) affecting potentially ALS-associated genes, including C9orf[72], TDP43, FUS, MATR3, UBQLN2, VCP and OPTN6–9. In this context, a recent large-scale genome-wide association study identified a common missense variant and several rare loss-of-function (LOF) mutations within the microtubule motor. In addition to the contribution of SNPs, which account for only a limited number of familial and sporadic
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