Rigorous attempts to define intermediate phenotypes that represent components of the underlying disease neurobiology are also necessary to develop a more therapeutically meaningful nosology, but this area has proven very challenging (67). One potential avenue is using more data-driven approaches in humans, such as genetic risk scores and Mendelian randomization based on the joint effects of multiple risk loci to refine causal relationships between disease and intermediate phenotypes (68). Moreover, specificity of action is a prerogative of neural development and neuronal circuits, not genes. Technologies that have brought activity in neuronal circuits under exogenous control repeatedly demonstrate the existence of circuits that are responsible for specific behaviors. Circuits and diseases that can be modeled in genetically tractable organisms permit hypothesis testing that draws on genetic results to propose genes for functional testing.
