Shared Genetic Networks in Schizophrenia and Bipolar Disorder: Hippocampal Volume-Mediated Neurobiological Mechanisms

Abstract Background Studies have shown similarities in clinical symptoms and biological markers between schizophrenia (SCZ) and bipolar disorder (BD). However, the impact of these shared genetic factors on the diseases remains poorly understood. Study Design We utilized the hippocampus volume (HIPV) as an auxiliary phenotype for identifying pleiotropic genetic loci associated with BD and SCZ. Using conditional/conjunctional false discovery rate approach to evaluate overlap in common genetic variants. We established co-expression networks of the overlapping genes in SCZ and BD using BrainSpan’s transcriptomes, and performed the gene-set analysis of each gene subnetwork with symptoms in SCZ. Results We identified several loci shared between SCZ and left HIPV (n = 8) and right HIPV (n = 13), BD and left HIPV (n = 1), and right HIPV (n = 3). Twenty-two and 70 candidate genes mapped by shared loci for BD and SCZ, respectively, and 20 overlapping genes in SCZ and BD. Functional enrichment analysis pointed to the 20 genes being associated with 16p11.2 proximal deletion syndrome. According to the brain transcriptome data, it was found that the 20 genes were enriched for the transcriptional co-expression profile in prenatal primary auditory cortex, inferolateral temporal cortex, inferior parietal cortex, and medial prefrontal cortex. Further gene-set analysis uncovered that the genes in the subnetwork of medial prefrontal cortex were significantly associated with negative symptom in SCZ. Conclusions The study indicated that SCZ and BD shared a genetic basis with HIPV, and the genetic overlaps suggested shared neurobiological mechanisms between the 2 disorders.