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Transl Psychiatry. 2018 May 24;8(1):105. doi: 10.1038/s41398-018-0154-2.

Convergent roles of de novo mutations and common variants in schizophrenia in tissue-specific and spatiotemporal co-expression network.

Jia P1, Chen X2, Fanous AH3,4,5,6, Zhao Z7,8,9.

Author information

1
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
2
Nevada Institute of Personalized Medicine and Department of Psychology, University of Nevada Las Vegas, Las Vegas, NV, USA.
3
Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
4
Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
5
Mental Health Service Line, Washington VA Medical Center, Washington, DC, USA.
6
Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA.
7
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA. zhongming.zhao@uth.tmc.edu.
8
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. zhongming.zhao@uth.tmc.edu.
9
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. zhongming.zhao@uth.tmc.edu.

Abstract

Genetic components susceptible to complex disease such as schizophrenia include a wide spectrum of variants, including common variants (CVs) and de novo mutations (DNMs). Although CVs and DNMs differ by origin, it remains elusive whether and how they interact at the gene, pathway, and network levels that leads to the disease. In this work, we characterized the genes harboring schizophrenia-associated CVs (CVgenes) and the genes harboring DNMs (DNMgenes) using measures from network, tissue-specific expression profile, and spatiotemporal brain expression profile. We developed an algorithm to link the DNMgenes and CVgenes in spatiotemporal brain co-expression networks. DNMgenes tended to have central roles in the human protein-protein interaction (PPI) network, evidenced in their high degree and high betweenness values. DNMgenes and CVgenes connected with each other significantly more often than with other genes in the networks. However, only CVgenes remained significantly connected after adjusting for their degree. In our gene co-expression PPI network, we found DNMgenes and CVgenes connected in a tissue-specific fashion, and such a pattern was similar to that in GTEx brain but not in other GTEx tissues. Importantly, DNMgene-CVgene subnetworks were enriched with pathways of chromatin remodeling, MHC protein complex binding, and neurotransmitter activities. In summary, our results unveiled that both DNMgenes and CVgenes contributed to a core set of biologically important pathways and networks, and their interactions may attribute to the risk for schizophrenia. Our results also suggested a stronger biological effect of DNMgenes than CVgenes in schizophrenia.

PMID:
29799522
PMCID:
PMC5967316
DOI:
10.1038/s41398-018-0154-2
[Indexed for MEDLINE]
Free PMC Article

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