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

Full description

Saved in:
Bibliographic Details
Published inBrain (London, England : 1878) Vol. 140; no. 6; pp. 1611 - 1618
Main Authors Morgan, Sarah, Shatunov, Aleksey, Sproviero, William, Jones, Ashley R, Shoai, Maryam, Hughes, Deborah, Al Khleifat, Ahmad, Malaspina, Andrea, Morrison, Karen E, Shaw, Pamela J, Shaw, Christopher E, Sidle, Katie, Orrell, Richard W, Fratta, Pietro, Hardy, John, Pittman, Alan, Al-Chalabi, Ammar
Format Journal Article
LanguageEnglish
Published England Oxford University Press 01.06.2017
Subjects
Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis - genetics
Female
Genetic Association Studies
Genetic Variation
High-Throughput Nucleotide Sequencing
Humans
Male
Middle Aged
Multifactorial Inheritance
Original
United Kingdom
Young Adult
neurodegeneration
polygenic inheritance
amyotrophic lateral sclerosis
complex trait
association study
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
These authors contributed equally to this work.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awx082