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Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson’s disease revealed different epigenetic patterns in peripheral blood mononuclear cells

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Abstract

Numerous studies have elucidated the genetics of Parkinson’s disease; however, the aetiology of the majority of sporadic cases has not yet been resolved. We hypothesized that epigenetic variations could be associated with PD and evaluated the DNA methylation pattern in PD patients compared to brothers or twins without PD. The methylation of DNA from peripheral blood mononuclear cells of 62 discordant siblings including 24 monozygotic twins was characterized with Illumina DNA Methylation 450K bead arrays and subsequently validated in two independent cohorts: 221 PD vs. 227 healthy individuals (cohort 1) applying Illumina’s VeraCode and 472 PD patients vs. 487 controls (cohort 2) using pyrosequencing. We choose a delta beta of >15 % and selected 62 differentially methylated CpGs in 51 genes from the discordant siblings. Among them, three displayed multiple CpGs per gene: microRNA 886 (MIR886, 10 CpGs), phosphodiesterase 4D (PDE4D, 2 CpGs) and tripartite motif-containing 34 (TRIM34, 2 CpGs). PDE4D was confirmed in both cohorts (p value 2.44e−05). In addition, for biomarker construction, we used the penalized logistic regression model, resulting in a signature of eight CpGs with an AUC of 0.77. Our findings suggest that a distinct level of PD susceptibility stems from individual, epigenetic modifications of specific genes. We identified a signature of CpGs in blood cells that could separate control from disease with a reasonable discriminatory power, holding promise for future epigenetically based biomarker development.

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Abbreviations

AUC:

Area under the curve

CpG:

Cytosine and guanine separated by one phosphate

GWAS:

Genome-wide association studies

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine

MZ:

Monozygotic

PD:

Parkinson’s disease

PBMC:

Peripheral blood mononuclear cells

ROC:

Receiver-operating characteristic

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Acknowledgments

We would like to thank all of the participants, PD patients and twins for their voluntary contribution to this research project. We would also like to thank the staff of the Department of Twin Research (DTR) of the King’s College in London for their help and support in undertaking this project, with special thanks to Victoria Vazquez. The Wellcome Trust provides core support for DTR. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking [Aetionomy [grant number 115568]), the BMBF/ANR through the EpiPD (Epigenomics of Parkinson’s disease) project, under the auspices of the bilateral Epigenomics of Common and Age-related Diseases Programme (grant no. 01KU1403B to UW and ANR-13-EPIG-0003-05 to JT) and the ParkinsonFonds (research grant to OK). The excellent technical work of Anne Hanke, Hassan Khazneh and Sabine Proske-Schmitz is gratefully acknowledged.

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Correspondence to Oliver Kaut.

Ethics declarations

The experiments were undertaken with the understanding and written consent of each subject. The study conforms to the World Medical Association Declaration of Helsinki. The Ethics Committee of the Medical Faculty of the University of Bonn approved this study (No. 51/00, 6 July 2000).

Conflict of interest

The authors declare that they have no conflict of interest.

Authors’ contributions

OK conceived the study, collected MZ twin probes, participated in pyrosequencing, performed statistical analysis and interpretation of data and wrote the manuscript.

IS participated in the sequence alignment, designed primers and performed pyrosequencing.

JT performed statistical analysis and provided figures.

FB performed statistical analysis.

YL performed statistical analysis.

PH participated in the sequence alignment and helped to draft the manuscript.

SW collected the data and probes and performed the VeraCode array.

MR participated in the study design and helped to draft the manuscript.

VV collected MZ twin probes, contributed to data interpretation and helped to draft the manuscript.

HF performed statistical analysis and provided figures.

UW conceived the study, contributed to data interpretation and wrote the manuscript.

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Kaut, O., Schmitt, I., Tost, J. et al. Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson’s disease revealed different epigenetic patterns in peripheral blood mononuclear cells. Neurogenetics 18, 7–22 (2017). https://doi.org/10.1007/s10048-016-0497-x

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  • DOI: https://doi.org/10.1007/s10048-016-0497-x

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