Abstract
BackgroundRecent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant. MethodsWe aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage. ResultsWe observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes. ConclusionsOur results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.
Highlights
Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges
By integrating developmental transcriptomic data of the human brain with genome-wide association studies (GWASs) data of genetic risk in schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), we aimed to identify time points at which gene sets implicated in risk for psychiatric disorders are most strongly expressed, in view of highlighting periods when key biological pathways may preferentially confer risk to these disorders
Because of redundancy between Gene Ontology (GO) terms, we used conditional analyses to select gene sets with independent associations. This procedure yielded six sets independently associated with schizophrenia (Table S2A in Supplement 2) and two sets independently associated with BD (Table S2B in Supplement 2)
Summary
Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. These studies do not reveal the developmental time point(s) at which these pathways are relevant. CONCLUSIONS: Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. They indicate key time points and potential targets for disorder-specific therapeutic interventions
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