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 postmortem 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 shows 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 skeleton 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 dataset of 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.

Gastroenterology issues in schizophrenia: Why the gut matters

“…Daneman and Rescigno (2009) provide an exquisite review of how the gut immune barrier and the blood-brain barrier are functionally and structurally similar [68]. In this section, we will focus on the environmental perturbation of these cytoskeletal architectures, but it is duly noted that a number of genes involved in barrier structures have been identified as susceptibilitiy loci for schizophrenia, such as the tight junction protein claudin-5, actin and other cytoskeletal elements, haptoglobin and nitric oxide synthetase [69][70][71][72].…”

The Proteome of BLOC-1 Genetic Defects Identifies the Arp2/3 Actin Polymerization Complex to Function Downstream of the Schizophrenia Susceptibility Factor Dysbindin at the Synapse

“…These ontologically informed pathways often implicate synapse function as a pathogenesis mechanism. Individual genetic risk loci are likely to influence the expression of multiple proteins encoded by genes other than the affected locus (Picotti et al, 2013;Wu et al, 2013;Albert et al, 2014). These proteins downstream of a single risk allele could map within a protein complex, cellular pathway, or organelle.…”

Genetic studies of schizophrenia: an update

“…MIR137 targets multiple genes involved in SCZ, bipolar disorder, and autism [86][87][88] . While the extent of sharing between these disorders may differ, the pleiotropic effects seem to extend beyond these traditional psychiatric disorders [89][90][91][92] .…”