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Mol Psychiatry. 2019 Apr 11. doi: 10.1038/s41380-019-0416-2. [Epub ahead of print]

Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders.

Xia Y1,2, Dai R1,2, Wang K1, Jiao C2, Zhang C3, Xu Y4, Li H4, Jing X4, Chen Y1, Jiang Y1,5, Kopp RF2, Giase G6, Chen C7,8,9, Liu C10,11,12.

Author information

1
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
2
Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY, USA.
3
Department of Neuroscience, State University of New York Upstate Medical University, Syracuse, NY, USA.
4
Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
5
Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.
6
Department of Public Health, University of Illinois at Chicago, Chicago, IL, USA.
7
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China. chenchao@sklmg.edu.cn.
8
Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY, USA. chenchao@sklmg.edu.cn.
9
National Clinical Research Center for Geriatric Disorders, the Xiangya Hospital, Central South University, Changsha, Hunan, China. chenchao@sklmg.edu.cn.
10
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China. liuch@upstate.edu.
11
Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY, USA. liuch@upstate.edu.
12
School of Psychology, Shaanxi Normal University, Xi'an, China. liuch@upstate.edu.

Abstract

Many psychiatric disorders are characterized by a strong sex difference, but the mechanisms behind sex-bias are not fully understood. DNA methylation plays important roles in regulating gene expression, ultimately impacting sexually different characteristics of the human brain. Most previous literature focused on DNA methylation alone without considering the regulatory network and its contribution to sex-bias of psychiatric disorders. Since DNA methylation acts in a complex regulatory network to connect genetic and environmental factors with high-order brain functions, we investigated the regulatory networks associated with different DNA methylation and assessed their contribution to the risks of psychiatric disorders. We compiled data from 1408 postmortem brain samples in 3 collections to identify sex-differentially methylated positions (DMPs) and regions (DMRs). We identified and replicated thousands of DMPs and DMRs. The DMR genes were enriched in neuronal related pathways. We extended the regulatory networks related to sex-differential methylation and psychiatric disorders by integrating methylation quantitative trait loci (meQTLs), gene expression, and protein-protein interaction data. We observed significant enrichment of sex-associated genes in psychiatric disorder-associated gene sets. We prioritized 2080 genes that were sex-biased and associated with psychiatric disorders, such as NRXN1, NRXN2, NRXN3, FDE4A, and SHANK2. These genes are enriched in synapse-related pathways and signaling pathways, suggesting that sex-differential genes of these neuronal pathways may cause the sex-bias of psychiatric disorders.

PMID:
30976086
DOI:
10.1038/s41380-019-0416-2

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