The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of subjects with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, they found that ∼20% of schizophrenia loci have variants that may contribute to altered gene expression and liability. Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.

SCHIZOPHRENIA IS a chronic, debilitating psychiatric illness affecting approximately 1% of the general population. Clinical manifestations appear during late adolescence to early adulthood. Characteristic features of schizophrenia include a mixture of positive (distortions of inferential thought, perception, language/communication, and behavioral monitoring) and negative (blunted affect, alogia, and avolition) symptoms.¹ The temporal lobe, including the hippocampus, subiculum, and entorhinal cortex (EC), is a primary brain region associated with schizophrenia. The EC is integral to the function of the hippocampus, regulating the interaction of the hippocampus with other brain regions. Disruption of neuronal functioning in this region could affect information processing between the hippocampus and various cortical areas. Dysregulation of temporal lobe function is associated with symptoms that are similar to those found in individuals diagnosed as having schizophrenia. For example, results of functional neuroimaging studies and neuropsychological assessment of patients with schizophrenia report significant deficits in temporal lobe function.² Results of most structural imaging studies in schizophrenia indicate a slight but significant reduction in hippocampal volume,^3-11 although other studies failed to observe these differences.^12-14 A relative paucity of neurodegeneration, cell death, or gliosis is observed in temporal lobe structures in schizophrenic brains.^15,16

In screening amplified poly(A) mRNA from hippocampal dendrites and growth cones in culture to determine candidates for local translation, we found that select transcription factor mRNAs were present. We hypothesized that synthesis of transcription factor proteins within dendrites would provide a direct signaling pathway between the distal dendrite and the nucleus resulting in modulation of gene expression important for neuronal differentiation. To evaluate this possibility, radiolabeled amplified antisense RNA was used to probe slot blots of transcription factor cDNAs as well as arrayed blots of zinc finger transcription factors. The mRNAs encoding the cAMP response element binding protein (CREB), zif 268, and one putative transcription factor were detected. We expanded upon these results showing that CREB protein is present in dendrites, that translation of CREB mRNA in isolated dendrites is feasible and that CREB protein found in dendrites can interact with the cis-acting cyclic AMP reponse element DNA sequence by using an in situ Southwestern assay. Further, CREB protein in dendrites is not transported to this site from the cell body because fluorescently tagged CREB microperfused into the soma did not diffuse into the dendrites. In addition, CREB protein microperfused into dendrites was rapidly transported to the nucleus, its likely site of bioactivity. Lastly, by using the isolated dendrite system we show that phosphorylation of Ser-133 on CREB protein can occur in isolated dendrites independent of the nucleus. These data provide a regulatory pathway in which transcription factors synthesized and posttranslationally modified in dendrites directly alter gene expression bypassing the integration of signal transduction pathways that converge on the nucleus.