How Might We Get from Genes to Circuits to Disease?

Recent advances in the identification of risk genes for psychiatric disorders have set the stage for functional interrogation of disease related-circuits and underlying mechanisms of pathophysiology. Still, investigators face significant challenges: (a) hundreds of genes may contribute to pathogenesis of a given disorder (polygenicity and genetic heterogeneity), (b) risk alleles may only cause the disease in combination with other factors (reduced penetrance), and (c) commonly used rodent models may have significant limitations in studying psychiatric disorders, due to differences in brain structure and function between rodents and humans. To address these challenges, high-throughput functional assays should be developed in combination with induced pluripotent stem cells (iPSC) technology and novel genome-engineering technologies, as these will help identify common pathways and mechanisms onto which multiple risk genes may converge. To overcome limitations of current animal models in psychiatric research, novel genome-editing technologies provide an opportunity to generate better animal models (e.g., the common marmoset) to dissect disease-relevant circuit dysfunction. Finally, powerful new tools (e.g., CLARITY, dense neural circuit reconstruction, and optogenetics) may help identify and test the relationship between distinct circuit defects and abnormal behaviors observed in these animal models. Such approaches are needed to span the gap between emerging genetic information and the symptomatic description of neuropsychiatric disorders.