Systematic discovery of signaling pathways linking immune activation to schizophrenia

Yue Gao; Yanjun Li; ShuangYan Li; Xiaozhen Liang; Zhonglu Ren; Xiaoxue Yang; Bin Zhang; Yanhui Hu; Xinping Yang

doi:10.1016/j.isci.2021.103209

Systematic discovery of signaling pathways linking immune activation to schizophrenia

iScience. 2021 Oct 2;24(11):103209. doi: 10.1016/j.isci.2021.103209. eCollection 2021 Nov 19.

Authors

Yue Gao^{1

2

3

4}, Yanjun Li^{1

3

4}, ShuangYan Li⁵, Xiaozhen Liang¹, Zhonglu Ren¹, Xiaoxue Yang¹, Bin Zhang⁵, Yanhui Hu², Xinping Yang^{1

3

4}

Affiliations

¹ Center for Genetics and Developmental Systems Biology, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
² Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
³ Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence and Guangdong Key Laboratory of Psychiatric Disorders, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
⁴ Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
⁵ Department of Psychiatry, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Abstract

Immune activation has been shown to play a critical role in the development of schizophrenia; however its underlying mechanism remains unknown. Our report demonstrates a high-quality protein interaction network for schizophrenia (SCZ Network), constructed using our "neighborhood walk" approach in combination with "random walk with restart". The spatiotemporal expression pattern of the genes in this disease network revealed two developmental stages sensitive to perturbation by immune activation: mid-to late gestation, and adolescence. Furthermore, we induced immune activation at these stages in mice, carried out transcriptome sequencing on the mouse brains, and illustrated clear potential molecular pathways and key regulators correlating maternal immune activation during gestation and an increased risk for schizophrenia after a second immune activation at puberty. This work provides not only valuable resources for the study on molecular mechanisms underlying schizophrenia, but also a systematic strategy for the discovery of molecular pathways of complex mental disorders.

Keywords: Biocomputational method; Bioinformatics; Clinical neuroscience; Immunology; Systems biology.