Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder

Abstract

Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental disorders with high heritability. Clinicians have long noticed the similarities of clinic symptoms between these disorders. In recent years, accumulating evidence indicates some shared genetic liabilities. However, what is shared remains elusive. In this study, we conducted whole transcriptome analysis of post-mortem brain tissues (cingulate cortex) from SCZ, BPD and control subjects, and identified differentially expressed genes in these disorders. We found 105 and 153 genes differentially expressed in SCZ and BPD, respectively. By comparing the t-test scores, we found that many of the genes differentially expressed in SCZ and BPD are concordant in their expression level (q⩽0.01, 53 genes; q⩽0.05, 213 genes; q⩽0.1, 885 genes). Using genome-wide association data from the Psychiatric Genomics Consortium, we found that these differentially and concordantly expressed genes were enriched in association signals for both SCZ (P<10(-7)) and BPD (P=0.029). To our knowledge, this is the first time that a substantially large number of genes show concordant expression and association for both SCZ and BPD. Pathway analyses of these genes indicated that they are involved in the lysosome, Fc gamma receptor-mediated phagocytosis, regulation of actin cytoskeleton pathways, along with several cancer pathways. Functional analyses of these genes revealed an interconnected pathway network centered on lysosomal function and the regulation of actin cytoskeleton. These pathways and their interacting network were principally confirmed by an independent transcriptome sequencing data set of the hippocampus. Dysregulation of lysosomal function and cytoskeleton remodeling has direct impacts on endocytosis, phagocytosis, exocytosis, vesicle trafficking, neuronal maturation and migration, neurite outgrowth and synaptic density and plasticity, and different aspects of these processes have been implicated in SCZ and BPD.

Figure 1

Correlation of gene expression between schizophrenia and bipolar disorder. T-test scores from differential expression analyses of schizophrenia and bipolar disorder were plotted. This plot is a typical among the 100 trials in which half of the control samples (n=26) were randomly selected for controls for schizophrenia and the other half for bipolar disorder. The correlation coefficient (r = 0.285 ± 0.10) was the median of these 100 trials.

Figure 2

Pathway interaction networks for differentially and concordantly expressed genes (DCEG) and top-ranked candidates between schizophrenia and bipolar disorder. A. Interaction network constructed from the pathways significantly enriched with DCEGs from the discovery sample. Node size and edge width are proportional to pathway enrichment significance level and pathway interaction significance level, respectively. Fc gamma receptor mediated phagocytosis, regulation of actin cytoskeleton, and axon guidance pathways had the strongest mutual interactions, and the triangle formed by these three pathways were highlighted by solid, red edges. B. Interaction network constructed from the top-ranked DCEG candidates from the replication sample. The legends were the same as in A. The interactions between the regulation of actin cytoskeleton, axon guidance, Fc gamma R-mediated phagocytosis and pancreatic cancer were replicated between the discovery and replication samples.

Figure 3

Biological processes implicated from the pathways enriched with differentially and coordinately expressed genes in schizophrenia and bipolar disorder. The solid arrows indicate known regulatory relationships. The dashed arrows denote relationships with some unknown links. Double-lined arrows denote the interacting relationships identified in this study. Red color denotes differentially and coordinately expressed genes in schizophrenia and bipolar disorder. L, ligand; N, neurophilin; P, plexin; and S, semaphorin.