Identification of epilepsy related pathways using genome-wide DNA methylation measures: A trio-based approach

PLoS One. 2019 Feb 8;14(2):e0211917. doi: 10.1371/journal.pone.0211917. eCollection 2019.

Abstract

Genetic generalized epilepsies (GGE) are genetically determined, as their name implies and they are clinically characterized by generalized seizures involving both sides of the brain in the absence of detectable brain lesions or other known causes. GGEs are yet complex and are influenced by many different genetic and environmental factors. Methylation specific epigenetic marks are one of the players of the complex epileptogenesis scenario leading to GGE. In this study, we have set out to perform genome-wide methylation profiling to analyze GGE trios each consisting of an affected parent-offspring couple along with an unaffected parent. We have developed a novel scoring scheme within trios to categorize each locus analyzed as hypo or hypermethylated. This stringent approach classified differentially methylated genes in each trio and helped us to produce trio specific and pooled gene lists with inherited and aberrant methylation levels. In order to analyze the methylation differences from a boarder perspective, we performed enrichment analysis with these lists using the PANOGA software. This collective effort has led us to detect pathways associated with the GGE phenotype, including the neurotrophin signaling pathway. We have demonstrated a trio based approach to genome-wide DNA methylation analysis that identified individual and possibly minor changes in methylation marks that could be involved in epileptogenesis leading to GGE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • DNA Methylation*
  • Electroencephalography
  • Epigenesis, Genetic*
  • Epilepsy, Generalized / diagnostic imaging
  • Epilepsy, Generalized / genetics*
  • Epilepsy, Generalized / metabolism
  • Epilepsy, Generalized / physiopathology
  • Female
  • Gene Expression Profiling
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genome, Human*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Inheritance Patterns
  • Male
  • Metabolic Networks and Pathways / genetics
  • Nerve Growth Factors / genetics*
  • Nerve Growth Factors / metabolism
  • Nuclear Family
  • Phenotype

Substances

  • Nerve Growth Factors

Grants and funding

This work was supported by the grants of The Scientific and Technology Research Council of Turkey (TUBITAK) Project Number: IntenC-109S218 and Scientific Research Projects Coordination Unit of Istanbul University, Project Number: ONAP-11021. Biobanking support was given by Istanbul Development Agency (Project Number: TR10/15/YNK/0093). OO, EE and SAUI had been fellows of TUBITAK-IntenC project.