Journal
BRAIN
Volume 140, Issue -, Pages 1611-1618Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awx082
Keywords
amyotrophic lateral sclerosis; neurodegeneration; complex trait; polygenic inheritance; association study
Categories
Funding
- MND Association
- Wellcome Trust
- JPND (United Kingdom)
- JPND (Medical Research Council) [MR/L501529/1]
- JPND (Economic and Social Research Council) [ES/L008238/1]
- National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust
- King's College London
- European Community [259867]
- Horizon Programme (H-PHC-two-stage) [633413]
- Economic and Social Research Council [ES/L008238/1] Funding Source: researchfish
- Medical Research Council [MR/L021803/1, G1100695, G0300329, G0600974, G0500289B, MR/L501529/1, G0500289, MR/M008606/1, G0900635, MC_G1000733, G0900688] Funding Source: researchfish
- Motor Neurone Disease Association [Fratta/Jan15/946-795, Malaspina/Apr13/817-791, Shaw/Nov14/985-797, AlChalabi-Dobson/Apr14/829-791, Jones/Oct15/958-799, Shaw/Apr15/970-797] Funding Source: researchfish
- ESRC [ES/L008238/1] Funding Source: UKRI
- MRC [MR/K01417X/1, MR/J004758/1, G1001253, G0901254, G0600974, MR/L021803/1, G0300329, G1100695, G0900635, G0500289, G0900688, G0701075, MC_G1000733, MR/M008606/1] Funding Source: UKRI
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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.
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