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Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.

Original publication

DOI

10.1093/brain/awx082

Type

Journal article

Journal

Brain

Publication Date

01/06/2017

Volume

140

Pages

1611 - 1618

Keywords

amyotrophic lateral sclerosis, association study, complex trait, neurodegeneration, polygenic inheritance, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Female, Genetic Association Studies, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Multifactorial Inheritance, United Kingdom, Young Adult