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Brain. 2017 Jun 1;140(6):1611-1618. doi: 10.1093/brain/awx082.

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

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Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, SE5 9RX, UK.
Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, North-East London and Essex Regional Motor Neuron Disease Care Centre, London, E1 2AT, UK.
Faculty of Medicine, University of Southampton, MP801 University Hospital Southampton NHS Foundation Trust, SO16 6YD, UK.
Sheffield Institute for Translational Neuroscience (SiTraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
Department of Clinical Neuroscience, UCL Institute of Neurology, Rowland Hill Street, London, NW3 2PF, UK.
Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.


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.


amyotrophic lateral sclerosis; association study; complex trait; neurodegeneration; polygenic inheritance

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