An integrative gene network-based approach to uncover the cellular and molecular infrastructures of schizophrenia

Abstract Aims High phenotypic and endophenotypic heritability of schizophrenia indicates substantial involvement of genetic elements in the occurrence of this disorder. Multiplicity of hypotheses about the genetic basis of schizophrenia pathogenesis suggests that there is still no integrated image from cellular and molecular infrastructure of this disorder. Materials and methods Here, we aimed to gain an integrated insight into the genetic basis of schizophrenia through gene set enrichment and network analysis to find the most important developmental stages/brain regions, chromosomal locations and metabolic pathways involved in the pathogenesis of schizophrenia. We investigated major mental disorders whose genetic bases are significantly overlapping with the schizophrenia gene set. Key findings Enrichment analyses uncovered 60 developmental stages/brain regions, 21 chromosomal hotspots and 16 pathways which are significantly associated with the found gene set. Our results demonstrated early mid-fetal/cortex as the most prominent developmental stage/brain region, chr16q22 as the most significant cytoband and the neuroactive ligand-receptor interaction as the most central pathway associated with schizophrenia. Further analyses revealed that autistic disorder has the most shared genes with schizophrenia. Moreover, mitogen-activated protein kinase-3 (MAPK3), calcium voltage-gated channel subunit alpha1 C (CACNA1C), solute carrier family 6 member 4 (SLC6A4) and 5-hydroxytryptamine receptor 2A (HTR2A) genes are the most central genes in the pathogenesis of schizophrenia. Significance In addition to summarizing what has been found on schizophrenia-associated genes in an integrative holistic framework, our results may help identify principle schizophrenia-associated cellular and molecular infrastructures, and provide support for further investigation on potential diagnostic and therapeutic biomarkers for schizophrenia.