What genes are differentially expressed in individuals with schizophrenia? A systematic review

Abstract

Schizophrenia is a severe, complex mental disorder characterized by a combination of positive symptoms, negative symptoms, and impaired cognitive function. Schizophrenia is highly heritable (~80%) with multifactorial etiology and complex polygenic genetic architecture. Despite the large number of genetic variants associated with schizophrenia, few causal variants have been established. Gaining insight into the mechanistic influences of these genetic variants may facilitate our ability to apply these findings to prevention and treatment. Though there have been more than 300 studies of gene expression in schizophrenia over the past 15 years, none of the studies have yielded consistent evidence for specific genes that contribute to schizophrenia risk. The aim of this work is to conduct a systematic review and synthesis of case-control studies of genome-wide gene expression in schizophrenia. Comprehensive literature searches were completed in PubMed, EmBase, and Web of Science, and after a systematic review of the studies, data were extracted from those that met the following inclusion criteria: human case-control studies comparing the genome-wide transcriptome of individuals diagnosed with schizophrenia to healthy controls published between January 1, 2000 and June 30, 2020 in the English language. Genes differentially expressed in cases were extracted from these studies, and overlapping genes were compared to previous research findings from the genome-wide association, structural variation, and tissue-expression studies. The transcriptome-wide analysis identified different genes than those previously reported in genome-wide association, exome sequencing, and structural variation studies of schizophrenia. Only one gene, GBP2, was replicated in five studies. Previous work has shown that this gene may play a role in immune function in the etiology of schizophrenia, which in turn could have implications for risk profiling, prevention, and treatment. This review highlights the methodological inconsistencies that impede valid meta-analyses and synthesis across studies. Standardization of the use of covariates, gene nomenclature, and methods for reporting results could enhance our understanding of the potential mechanisms through which genes exert their influence on the etiology of schizophrenia. Although these results are promising, collaborative efforts with harmonization of methodology will facilitate the identification of the role of genes underlying schizophrenia.

Fig. 1. PRISMA flow diagram.

The flow of information through the different phases of this systematic review, and it maps out the number of records identified, screened, included, and excluded.

Fig. 2. Differentially expressed genes by study and tissue source.

Genes that were reported as having different expression levels in individuals with and without schizophrenia in four (blue) or five (purple) studies are shown, with the lighter color representing consistent direction of effect and the darker color representing inconsistent directions of effect across the indicated studies. The first panel shows the studies that measured expression in blood samples, the middle panel shows studies in which expression was measured in brain tissue, and the third panel shows studies completed in other tissue types (skin fibroblasts, lymphoblastoid cell lines).

Fig. 3. Schizophrenia gene expression tissue specificity.

The -log 10 P value is provided for each of the 54 tissue types of the Genotype-Tissue Expression (GTEx) project v8 data, indicating whether the list of 160 genes reported as differentially expressed in individuals with schizophrenia is enriched for genes expressed in that tissue. Tissues with significant enrichment at a Bonferroni corrected P value < 0.05 are shown in red. The top panel shows upregulated differentially expressed genes (DEG), the middle panel shows downregulated DEG, and the bottom panel shows DEG in both directions.