Intermediate phenotypes in psychiatric disorders.

A. From genes to behavior. Genes encode for molecules, not specific symptoms. The abnormal behaviors observed in psychiatric disorders (such as delusions, hallucinations and cognitive deficits in schizophrenia) are the product of intermediate steps that occur between genes and behavior, such as cell activity and neural circuits. An intermediate phenotype is a heritable trait that is located on the pathogenesis path from genetic predisposition to psychopathology and is likely associated with a more basic and proximal etiological process and therefore more amenable to genetic investigation. B. Genetic risk on vulnerable brain circuits. B1. Identification of neuroimaging intermediate phenotypes – which are alterations in neural circuit functions in patients with psychiatric disorders as well as in high genetic risk subjects (i.e. unaffected relatives). B2. Imaging genetics defines neural systems that are modulated by genetic variations, including genetic variations that have been associated with increased risk for psychiatric disorders. B3. To increase the probability that the observed biological modulation by the risk genetic variation is the mechanism through which that gene increases the risk for a psychiatric disorder, it is important to demonstrate that the gene modulates a neuroimaging intermediate phenotype.

Genetic modulation on vulnerable circuitsA. Working memory. Most brain areas reported altered in patients and their healthy relatives during working memory task are also modulated by a number of risk genes explored with the same paradigm (red fields with square dots) (DLPFC, VLPFC, ACC, parietal cortex, and HF). Many other effects of genes during working memory paradigms have not been show to be intermediate phenotypes (striatum, basal ganglia, subgenual ACC, insula, BA10, BA 4/6, cerebellum) (blue fields). B. Cognitive control circuit. Several brain areas within the cognitive control circuit have been reported to be modulated by risk genes during cognitive control processing (PFC, especially ACC, superior temporal gyrus, parietal cortex, and cerebellum). Among these, only PFC (DLPFC, VLPFC and ACC) and parietal cortex have been consistently reported being altered in patients with schizophrenia and their unaffected relatives with cognitive control paradigms (red fields with square dots). Striatum and middle temporal gyrus (BA 21) have been reported altered in patients with schizophrenia and their healthy relatives during cognitive control, although none of the risk genes studied so far have shown modulation of these regions (yellow fields with solid line). C. Episodic memory circuit. Studies of potential intermediate phenotypes during episodic memory paradigms are very few and the only area consistently reported altered in patients and in their unaffected relatives is the VLPFC, a region that has not been shown to be modulated by risk genes so far explored with this paradigm (yellow field with solid line). On the other hand, several risk genes have been reported to modulate hippocampal activity during episodic memory, as well as DLPFC, ACC, insula, cerebellum, temporal, parietal, and occipital cortices, all regions whose role as intermediate phenotypes during episodic memory in schizophrenia has not been convincingly demonstrated (blue fields). Thus, there are no brain regions yet that show overlap between the two areas of research (no red fields). D. Verbal fluency circuit. Right IFG has been reported altered in patients with schizophrenia and their healthy relatives during verbal fluency paradigms. This same area has not been shown to be modulated by risk genes (yellow field with solid line). Many other regions have been reported to be modulated by risk genes during verbal fluency related paradigms, but their role as intermediate phenotypes has not been consistently established (blue fields).For working memory and cognitive control, only brain areas that were reported consistently altered in at least three studies are presented as potential intermediate phenotypes (from Supplementary Table 1). For episodic memory and verbal fluency, given the paucity of studies, only brain areas with at least one replicated result are reported as intermediate phenotypes (from Supplementary Table 1). For list of genes showing modulation on each circuit, refer to Supplementary Table 2.