Characterization of genome-wide association study data reveals spatiotemporal heterogeneity of mental disorders

Psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BIP), major depressive disorder (MDD), attention deficit-hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) are often related to brain development. Both shared and unique biological and neurodevelopmental processes have been reported to be involved in these disorders.

In this work, we developed an integrative analysis framework to seek for the sensitive spatiotemporal point during brain development underlying each disorder. Specifically, we first identified spatiotemporal gene co-expression modules for four brain regions three developmental stages (prenatal, birth to 11 years old, and older than 13 years), totaling 12 spatiotemporal sites. By integrating GWAS summary statistics and the spatiotemporal co-expression modules, we characterized the risk genes and their co-expression partners for five disorders.

We found that SCZ and BIP, ASD and ADHD tend to cluster with each other and keep a distance from other psychiatric disorders. At the gene level, we identified several genes that were shared among the most significant modules, such as CTNNB1 and LNX1, and a hub gene, ATF2, in multiple modules. Moreover, we pinpointed two spatiotemporal points in the prenatal stage with active expression activities and highlighted one postnatal point for BIP. Further functional analysis of the disorder-related module highlighted the apoptotic signaling pathway for ASD and the immune-related and cell-cell adhesion function for SCZ, respectively.

Our study demonstrated the dynamic changes of disorder-related genes at the network level, shedding light on the spatiotemporal regulation during brain development.