A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK

Abstract

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.

Keywords: amyotrophic lateral sclerosis; association study; complex trait; neurodegeneration; polygenic inheritance.

Figure 1

Simplified flowchart describing the steps taken from sample to result in this study.

Figure 2

Schematic representation of the UTRs of TARDBP and FUS and the variants found in this study within cases (blue) and controls (black) in these regions. Variants within the 5’UTR are preceded with a minus while those contained in the 3’UTR are headed by an asterisk. This includes variants previously published in ALS marked in red (Supplementary Table 8).