Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression

Ingrid S. Tarr, Emily P. McCann, Beben Benyamin, Timothy J. Peters, Natalie A. Twine, Katharine Y. Zhang, Qiongyi Zhao, Zong-Hong Zhang, Dominic B. Rowe, Garth A. Nicholson, Denis Bauer, Susan J. Clark, Ian P. Blair, Kelly L. Williams

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. ALS exhibits high phenotypic variability including age and site of onset, and disease duration. To uncover epigenetic and transcriptomic factors that may modify an ALS phenotype, we used a cohort of Australian monozygotic twins (n = 3 pairs) and triplets (n = 1 set) that are discordant for ALS and represent sporadic ALS and the two most common types of familial ALS, linked to C9orf72 and SOD1. Illumina Infinium HumanMethylation450K BeadChip, EpiTYPER and RNA-Seq analyses in these ALS-discordant twins/triplets and control twins (n = 2 pairs), implicated genes with consistent longitudinal differential DNA methylation and/or gene expression. Two identified genes, RAD9B and C8orf46, showed significant differential methylation in an extended cohort of >1000 ALS cases and controls. Combined longitudinal methylation-transcription analysis within a single twin set implicated CCNF, DPP6, RAMP3, and CCS, which have been previously associated with ALS. Longitudinal transcriptome data showed an 8-fold enrichment of immune function genes and under-representation of transcription and protein modification genes in ALS. Examination of these changes in a large Australian sporadic ALS cohort suggest a broader role in ALS. Furthermore, we observe that increased methylation age is a signature of ALS in older patients.

LanguageEnglish
Article number8254
Pages1-17
Number of pages17
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 4 Jun 2019

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Monozygotic Twins
Amyotrophic Lateral Sclerosis
Methylation
Gene Expression
Genes
Motor Neurons
DNA Methylation
Transcriptome
Age of Onset
Epigenomics
Neurodegenerative Diseases
RNA
Phenotype

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this

Tarr, Ingrid S. ; McCann, Emily P. ; Benyamin, Beben ; Peters, Timothy J. ; Twine, Natalie A. ; Zhang, Katharine Y. ; Zhao, Qiongyi ; Zhang, Zong-Hong ; Rowe, Dominic B. ; Nicholson, Garth A. ; Bauer, Denis ; Clark, Susan J. ; Blair, Ian P. ; Williams, Kelly L. / Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression. In: Scientific Reports. 2019 ; Vol. 9, No. 1. pp. 1-17.
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Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression. / Tarr, Ingrid S.; McCann, Emily P.; Benyamin, Beben; Peters, Timothy J.; Twine, Natalie A.; Zhang, Katharine Y.; Zhao, Qiongyi; Zhang, Zong-Hong; Rowe, Dominic B.; Nicholson, Garth A.; Bauer, Denis; Clark, Susan J.; Blair, Ian P.; Williams, Kelly L.

In: Scientific Reports, Vol. 9, No. 1, 8254, 04.06.2019, p. 1-17.

Research output: Contribution to journalArticleResearchpeer-review

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AU - McCann, Emily P.

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AU - Twine, Natalie A.

AU - Zhang, Katharine Y.

AU - Zhao, Qiongyi

AU - Zhang, Zong-Hong

AU - Rowe, Dominic B.

AU - Nicholson, Garth A.

AU - Bauer, Denis

AU - Clark, Susan J.

AU - Blair, Ian P.

AU - Williams, Kelly L.

N1 - Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Y1 - 2019/6/4

N2 - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. ALS exhibits high phenotypic variability including age and site of onset, and disease duration. To uncover epigenetic and transcriptomic factors that may modify an ALS phenotype, we used a cohort of Australian monozygotic twins (n = 3 pairs) and triplets (n = 1 set) that are discordant for ALS and represent sporadic ALS and the two most common types of familial ALS, linked to C9orf72 and SOD1. Illumina Infinium HumanMethylation450K BeadChip, EpiTYPER and RNA-Seq analyses in these ALS-discordant twins/triplets and control twins (n = 2 pairs), implicated genes with consistent longitudinal differential DNA methylation and/or gene expression. Two identified genes, RAD9B and C8orf46, showed significant differential methylation in an extended cohort of >1000 ALS cases and controls. Combined longitudinal methylation-transcription analysis within a single twin set implicated CCNF, DPP6, RAMP3, and CCS, which have been previously associated with ALS. Longitudinal transcriptome data showed an 8-fold enrichment of immune function genes and under-representation of transcription and protein modification genes in ALS. Examination of these changes in a large Australian sporadic ALS cohort suggest a broader role in ALS. Furthermore, we observe that increased methylation age is a signature of ALS in older patients.

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