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Integrative co-methylation network analysis identifies novel DNA methylation signatures and their target genes in Alzheimer’s disease

  • Jun Pyo Kim
    Affiliations
    Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Medical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Bo-Hyun Kim
    Affiliations
    Department of Biomedical Engineering, Hanyang University, Seoul, Korea
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  • Paula J. Bice
    Affiliations
    Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
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  • Sang Won Seo
    Affiliations
    Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • David A. Bennett
    Affiliations
    Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
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  • Andrew J. Saykin
    Affiliations
    Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
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  • Kwangsik Nho
    Correspondence
    Corresponding Author: Kwangsik Nho, PhD, Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, 355 W 16th St., GH 4101, Indianapolis, Indiana, 46202, USA, Tel: 317-963-7503; Fax: 317-963-7547;
    Affiliations
    Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA
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      Abstract

      INTRODUCTION

      DNA methylation is a key epigenetic marker, and its alternations may be involved in Alzheimer’s disease. CpGs sharing similar biological functions or pathways tend to be co-methylated.

      METHODS

      We performed an integrative network-based DNA methylation analysis on two independent cohorts (N=941) using brain DNA methylation profiles and RNA-Seq as well as AD pathology data.

      RESULTS

      Weighted co-methylation network analysis identified six modules as significantly associated with neuritic plaque burden. Fifteen hub-CpGs including three novel CpGs were identified and replicated as being significantly associated with AD pathology. Furthermore, we identified and replicated four target genes (ATP6V1G2, VCP, RAD52, LST1) as significantly regulated by DNA methylation at hub-CpGs. In particular, VCP gene expression was also associated with AD pathology in both cohorts.

      DISCUSSION

      This integrative network-based multi-omics study provides compelling evidence for a potential role of DNA methylation alternations and their target genes in Alzheimer’s disease.

      Key words

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