Associations between DNA methylation and schizophrenia-related intermediate phenotypes - A gene set enrichment analysis

Johanna Hass, Esther Walton, Carrie Wright, Andreas Beyer, Markus Scholz, Jessica Turner, Jingyu Liu, Michael N. Smolka, Veit Roessner, Scott R. Sponheim, Randy L. Gollub, Vince D. Calhoun, Stefan Ehrlich

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22 Scopus citations


Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia.Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets.We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders.Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.

Original languageEnglish (US)
Pages (from-to)31-39
Number of pages9
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
StatePublished - Jun 3 2015

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health ( NIH/NCRR P41RR14075 , NIBIB 2R01EB000840 and COBRE 5P20RR021938/P20GM103472 ), U.S. Department of Energy ( DE-FG02-99ER62764 ), The Mind Research Network , Morphometry BIRN ( 1U24 , RR021382A ), Function BIRN ( U24RR021992-01 , NIH.NCRR MO1 RR025758-01 ), NARSAD Young Investigator Grant (SE), and the Deutsche Forschungsgemeinschaft (EH 367/5-1 ; Research Fellowship to SE). All funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Publisher Copyright:
© 2015 Elsevier Inc.


  • DNA methylation
  • GSEA
  • Intermediate phenotype
  • MicroRNA targets
  • Schizophrenia


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