In order to better understand how schizophrenia risk genetics operate at the cognitive and neural systems level, our recent work under this project has focused on (1) identifying novel phenotypes that distinguish both people with schizophrenia and unaffected family members from unrelated healthy individuals, (2) discovering associations between specific risk genes and schizophrenia-linked brain phenotypes, and (3) revealing important interactions between schizophrenia risk genetics and schizophrenia risk environmental exposures. Ongoing studies in these veins permit better understanding of heritable, trait-related abnormalities in schizophrenia, of the underlying molecular biology responsible for such abnormalities, and of strategies for resolving some of the illness heterogeneity that makes biological research so challenging. With respect to identifying illness-related phenotypes, we have shown that at least one measure of in vivo levels of GABA, a critical inhibitory neurotransmitter, measured in the dorsal anterior cingulate with MRS is reduced in both individuals with schizophrenia and their unaffected siblings. Moreover, this measure appears to be moderately heritable within families, possibly constituting an intermediate phenotype of modest effect size. This is in line with hypotheses of GABAergic disruption in schizophrenia primarily founded on post-mortem brain tissue investigations, and is in contrast to an important negative finding in which we confirmed an absence of MRS measured glutamate levels in the same brain region. Efforts to elaborate on these observations and, in the case of GABA, determine underlying genetic mechanisms are ongoing. In parallel, genetic work aimed at elucidating links between risk genes and risk-associated cognitive and neural signatures has been accelerating. This work offers the opportunity to provide biological validation to putative risk genes, thereby identifying the most promising causative molecular targets--a critical step for advancing research on a polygenic, heterogeneous illness such as schizophrenia. Earlier work by our group established a coherent, latent structure within our extensive cognitive measurements, identifying six domain composite factors, and a higher order factor reflecting general cognitive ability. Employing these indexes, we previously showed that a genetic variant related to sodium channel biology helps to explain the severe cognitive impairment in our schizophrenia sample, and also the attenuated impairment in their unaffected siblings. We subsequently demonstrated the molecular functionality of this variant through analyses of gene transcript expression in post-mortem brain tissue. Then, by leveraging our fMRI assays of brain function, we also tied this gene variant to prefrontal inefficiency during the Nback task, a heritable phenotype characterized by our group. In ongoing work to better understand the nature of this effect, directionally opposite effects on general cognition have now been confirmed in 531 healthy individuals from NIMH and two additional sites and extended, using resting state fMRI to show that those with cognitively advantageous genotypes may have greater interregional correspondence between two frontal brain structures central to general cognitive performance: the dorsolateral prefrontal cortex and dorsal anterior cingulate. Independent and collaborative work on the interaction between genetic predisposition and exposure to environmental factors previously associated with epidemiological risk for schizophrenia, such as early life exposure to an urban environment (urbanicity) and obstetrical complications also highlight the richness of the sample accumulated so far and the important scientific implications of our findings. For instance, we have now identified robust interactions between variation in the dopamine genes COMT, DRD1, and DRD2 on the one hand, and urbanicity on the other hand impacting prefrontal fMRI signal; the COMT findings have been replicated in two independent cohorts. In a similar fashion, we have identified an interaction between childhood urbanicity and the hippocampally-important gene, BDNF, that alters the hippocampal physiological read-out in two fMRI tasks. These data mark a major step forward in characterizing the coalescence of genetic and environmental factors on systems-level brain function, and studies are underway to better define how these factors operate in the context of schizophrenia.