Convergent Roles of De Novo Mutations and Common Variants in Schizophrenia in Tissue-specific and Spatiotemporal Co-expression Network

Authors

Peilin Jia, The University of Texas Health Science Center at HoustonFollow
Xiangning Chen, University of Nevada, Las VegasFollow
Ayman H. Fanous, Virginia Commonwealth University; Keck School of Medicine of the University of Southern California; Washington VA Medical Center; Georgetown University School of Medicine
Zhongming Zhao, The University of Texas Health Science Center at Houston; Vanderbilt University Medical CenterFollow

Document Type

Article

Publication Date

5-24-2018

Publication Title

Translational Psychiatry

Volume

8

First page number:

1

Last page number:

10

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.

Disciplines

Psychiatry and Psychology

File Format

application/pdf

File Size

1.425 Kb

Language

English

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Repository Citation

Jia, P., Chen, X., Fanous, A. H., Zhao, Z. (2018). Convergent Roles of De Novo Mutations and Common Variants in Schizophrenia in Tissue-specific and Spatiotemporal Co-expression Network. Translational Psychiatry, 8 1-10.
http://dx.doi.org/10.1038/s41398-018-0154-2