Journal article
MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
Brain (London, England : 1878), Vol.142(7), pp.1876-1886
07/2019
DOI: 10.1093/brain/awz115
PMCID: PMC6598626
PMID: 31216018
Abstract
A genome-wide association study recently identified an
MSH3/DHFR
locus associated with Huntington’s disease progression. Flower, Lomeikaite
et al.
identify tandem repeat variants at this locus, and show that a three-repeat allele is associated with reduced somatic expansion, delayed onset and slower progression in Huntington’s disease and myotonic dystrophy type 1.
The mismatch repair gene
MSH3
has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in
MSH3
/
DHFR
, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in
MSH3
exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (
P
= 0.004) and delayed disease onset (
P
= 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (
P
= 3.86 × 10
−7
) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with
MSH3
and
DHFR
expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased
MSH3
and
DHFR
expression are associated with disease progression. These results suggest that variation in the
MSH3
exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.
Details
- Title: Subtitle
- MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
- Creators
- Michael Flower - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKVilija Lomeikaite - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKMarc Ciosi - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKSarah Cumming - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKFernando Morales - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKKitty Lo - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKDavina Hensman Moss - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKLesley Jones - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKPeter Holmans - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKDarren G Monckton - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKSarah J Tabrizi - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKOPTIMISTIC ConsortiumTRACK-HD Investigators
- Contributors
- Hans J Johnson (Contributor) - University of Iowa, Electrical and Computer Engineering
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.142(7), pp.1876-1886
- DOI
- 10.1093/brain/awz115
- PMID
- 31216018
- PMCID
- PMC6598626
- NLM abbreviation
- Brain
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Publisher
- Oxford University Press
- Grant note
- ;
- Language
- English
- Date published
- 07/2019
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Psychiatry; The Iowa Institute for Biomedical Imaging; The Iowa Initiative for Artificial Intelligence; Iowa Informatics Initiative
- Record Identifier
- 9984221955402771
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