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Epigenome-wide analysis in newborn blood spots from monozygotic twins discordant for cerebral palsy reveals consistent regional differences in DNA methylation

Mohandas, Namitha, Bass-Stringer, Sebastian, Maksimovic, Jovana, Crompton, Kylie, Loke, Yuk J, Walstab, Janet, Reid, Susan M, Amor, David J, Reddihough, Dinah and Craig, Jeffrey M 2018, Epigenome-wide analysis in newborn blood spots from monozygotic twins discordant for cerebral palsy reveals consistent regional differences in DNA methylation, Clinical epigenetics, vol. 10, pp. 1-15, doi: 10.1186/s13148-018-0457-4.

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Title Epigenome-wide analysis in newborn blood spots from monozygotic twins discordant for cerebral palsy reveals consistent regional differences in DNA methylation
Author(s) Mohandas, Namitha
Bass-Stringer, Sebastian
Maksimovic, Jovana
Crompton, Kylie
Loke, Yuk J
Walstab, Janet
Reid, Susan M
Amor, David J
Reddihough, Dinah
Craig, Jeffrey M
Journal name Clinical epigenetics
Volume number 10
Article ID 25
Start page 1
End page 15
Total pages 15
Publisher BioMed Central
Place of publication London, Eng.
Publication date 2018
ISSN 1868-7075
1868-7083
Keyword(s) cerebral palsy
DNA methylation
inflammation
epigenetics
discordant twins
Summary Background: Cerebral palsy (CP) is a clinical description for a group of motor disorders that are heterogeneous with respect to causes, symptoms and severity. A diagnosis of CP cannot usually be made at birth and in some cases may be delayed until 2-3years of age. This limits opportunities for early intervention that could otherwise improve long-term outcomes. CP has been recorded in monozygotic twins discordant for the disorder, indicating a potential role of non-genetic factors such as intrauterine infection, hypoxia-ischaemia, haemorrhage and thrombosis. The aim of this exploratory study was to utilise the discordant monozygotic twin model to understand and measure epigenetic changes associated with the development of CP.

Methods:
We performed a genome-wide analysis of DNA methylation using the Illumina Infinium Human Methylation 450 BeadChip array with DNA from newborn blood spots of 15 monozygotic twin pairs who later became discordant for CP. Quality control and data preprocessing were undertaken using the minfi R package. Differential methylation analysis was performed using the remove unwanted variation (RUVm) method, taking twin pairing into account in order to identify CP-specific differentially methylated probes (DMPs), and bumphunter was performed to identify differentially methylated regions (DMRs).

Results: We identified 33 top-ranked DMPs based on a nominal p value cut-off of p < 1×10 -4 and two DMRs (p < 1×10 -3 ) associated with CP. The top-ranked probes related to 25 genes including HNRNPL, RASSF5, CD3D and KALRN involved in immune signalling pathways, in addition to TBC1D24, FBXO9 and VIPR2 previously linked to epileptic encephalopathy. Gene ontology and pathway analysis of top-ranked DMP-associated genes revealed enrichment of inflammatory signalling pathways, regulation of cytokine secretion and regulation of leukocyte-mediated immunity. We also identified two top-ranked DMRs including one on chromosome 6 within the promoter region of LTA gene encoding tumour necrosis factor-beta (TNF-β), an important regulator of inflammation and brain development. The second was within the transcription start site of the LIME1 gene, which plays a key role in inflammatory pathways such as MAPK signalling. CP-specific differential DNA methylation within one of our two top DMRs was validated using an independent platform, MassArray EpiTyper.

Conclusions:
Ours is the first epigenome-wide association study of CP in disease-discordant monozygotic twin pairs and suggests a potential role for immune dysfunction in this condition.
Language eng
DOI 10.1186/s13148-018-0457-4
Field of Research 111499 Paediatrics and Reproductive Medicine not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2018, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30109092

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.