Multidimensional integrative analyses identify CA4 as a potential schizophrenia driver gene

Gene expression studies have identified multiple dysregulated genes in brains of schizophrenia cases compared with controls. However, many dysregulated genes are not replicated or confirmed in independent cohorts and it remains a major challenge to identify genes whose altered expression have a causal role in schizophrenia. Here we conducted differential expression analysis in three large-scale independent expression datasets, including CommonMind Consortium (CMC, 258 cases and 279 controls), Lieber Institute for Brain Development (LIBD, 155 cases and 196 controls), and a GEO meta-analysis (140 cases and 134 controls), and identified 7 overlapping genes (CA4, SCN1B, IGFBP6, HR, GHR, DCP2, and FAM65B) that showed concordant expression change across all three datasets, strongly suggesting the pivotal role of these genes in schizophrenia. We also conducted Gene Ontology (GO) analysis and found that pathways related to nucleus, protein binding, mitochondria, among others, are dysregulated in schizophrenia cases in at least two independent datasets, indicating the potential causal role of these pathways in schizophrenia. Further we explored the genetic associations between these 7 overlapping genes and schizophrenia in populations of European ancestry, and found that a genetic variant (rs6503945) near CA4 showed association with schizophrenia risk (P = 3.17 × 10^-3). Finally, integrative analyses supported that CA4 is a risk gene whose genetically regulated downregulation is associated with schizophrenia risk. Collectively, these convergent and consistent results suggest that CA4 is a potential schizophrenia driven gene whose downregulation may have a causal role in schizophrenia pathogenesis.