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

被引：28

作者：

Hass, Johanna ^{[1
]}

Walton, Esther ^{[1
]}

Wright, Carrie ^{[2
,7
]}

Beyer, Andreas ^{[3
,4
]}

Scholz, Markus ^{[5
,6
]}

Turner, Jessica ^{[7
,8
]}

Liu, Jingyu ^{[7
,13
]}

Smolka, Michael N. ^{[9
]}

Roessner, Veit ^{[1
]}

Sponheim, Scott R. ^{[10
]}

Gollub, Randy L. ^{[11
,12
]}

Calhoun, Vince D. ^{[7
,13
]}

Ehrlich, Stefan ^{[1
,11
,12
]}

机构：

[1] Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Translat Dev Neurosci Sect, D-01307 Dresden, Germany

[2] Univ New Mexico, Hlth Sci Ctr, Dept Neurosci, Albuquerque, NM 87131 USA

[3] Tech Univ Dresden, Ctr Biotechnol, D-01307 Dresden, Germany

[4] Univ Cologne, CECAD, D-50931 Cologne, Germany

[5] Univ Leipzig, IMISE, D-04109 Leipzig, Germany

[6] Univ Leipzig, LIFE Leipzig Interdisciplinary Res Cluster Genet, D-04109 Leipzig, Germany

[7] Mind Res Network, Albuquerque, NM USA

[8] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA

[9] Tech Univ Dresden, Fac Med, Dept Psychiat, D-01307 Dresden, Germany

[10] Univ Minnesota, Dept Psychiat, Minneapolis VA Hlth Care Syst, Minneapolis, MN 55455 USA

[11] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

[12] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Charlestown, MA USA

[13] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA

来源：

PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY | 2015年 / 59卷

基金：

美国国家卫生研究院;

关键词：

DNA methylarion; GSEA; Intermediate phenotype; MicroRNA targets; Schizophrenia; ESTROGEN-RECEPTOR-ALPHA; WHITE-MATTER INTEGRITY; DORSOLATERAL PREFRONTAL CORTEX; GENOME-WIDE ASSOCIATION; WORKING-MEMORY; DIFFUSION TENSOR; BRAIN STRUCTURE; AUDITORY HALLUCINATIONS; CORTICAL THICKNESS; COMMON VARIANTS;

D O I：

10.1016/j.pnpbp.2015.01.006

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 01 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identity 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 (ERIIA4, 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. (C) 2015 Elsevier Inc. All rights reserved.

引用

页码：31 / 39

页数：9

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