Analysis of genome-wide copy number variation in Irish and Dutch ALS populations.

Amyotrophic lateral sclerosis (ALS) is an unrelenting neurodegenerative condition characterized by adult-onset loss of motor neurons. Genetic risk factors have been implicated in ALS susceptibility. Copy number variants (CNVs) account for more inter-individual genetic variation than SNPs and have the capacity to alter gene dose and phenotype. We sought to identify the contribution both of commonly polymorphic CNVs and rare ALS-specific CNVs to sporadic ALS (SALS). Using high-density genome-wide data from 408 Irish individuals and 868 Dutch individuals and the QuantiSNP CNV-detection algorithm, we showed that no common CNV locus is significantly associated with ALS risk. However, we identified 39 recurrent CNV loci and 16 replicated ALS-specific gene dose alterations that occur exclusively in patients with ALS and do not occur in more than 11 000 previously identified CNVs in the Database of Genomic Variation. Ataxin genes and the hereditary haemochromatosis locus were implicated along with ENSG00000176605, an uncharacterized gene on chromosome 14. Our data support the hypothesis that multiple rare CNVs may contribute risk for SALS. Future work should seek to profile the contribution of CNVs located in regions not covered on the present SNP platforms.