title: Associations between DNA methylation and schizophrenia-related intermediate phenotypes - a gene set enrichment analysis.
abstract: 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.
authors.affiliation: Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Hass
authors.affiliation: Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Walton
authors.affiliation: Department of Neurosciences, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA; The Mind Research Network, Albuquerque, NM USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Wright
authors.affiliation: Cellular Networks and Systems Biology, Biotechnology Center, TU Dresden, Dresden, Germany; University of Cologne, CECAD, Cologne, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beyer
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany; LIFE (Leipzig Interdisciplinary Research Cluster of Genetic Factors, Phenotypes and Environment), University of Leipzig, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
authors.affiliation: The Mind Research Network, Albuquerque, NM USA; Psychology Department, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Turner
authors.affiliation: The Mind Research Network, Albuquerque, NM USA; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM USA.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Smolka
authors.affiliation: Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Roessner
authors.affiliation: Minneapolis VA Health Care System, Department of Psychiatry, University of Minnesota, Minneapolis, MN USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Sponheim
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Boston, MA USA; MGH/MIT/HMS Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Gollub
authors.affiliation: The Mind Research Network, Albuquerque, NM USA; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM USA.
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.affiliation: Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany; Department of Psychiatry, Massachusetts General Hospital, Boston, MA USA; MGH/MIT/HMS Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA USA. Electronic address: transden.lab@uniklinikum-dresden.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrlich
mesh_terms: D000328:Adult; D019175:DNA Methylation / Q000235:genetics*; D016208:Databases, Factual / Q000706:statistics & numerical data; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006624:Hippocampus / Q000098:blood supply / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008609:Mental Status Schedule; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D010641:Phenotype; D021641:Recognition, Psychology; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D035683:MicroRNAs; D010100:Oxygen
keywords: DNA methylation; GSEA; Intermediate phenotype; MicroRNA targets; Schizophrenia