73Over 100 genetic loci harbor schizophrenia associated variants, yet how these common 74 variants confer risk is uncertain. The CommonMind Consortium has sequenced dorsolateral 75 prefrontal cortex RNA from schizophrenia cases (n=258) and control subjects (n=279), creating 76 the largest publicly available resource to date of gene expression and its genetic regulation; ~5 77 times larger than the latest release of GTEx. Using this resource, we find that ~20% of the 78 schizophrenia risk loci have common variants that could explain regulation of brain gene 79 expression. In five loci, these variants modulate expression of a single gene: FURIN, TSNARE1, 80 CNTN4, CLCN3 or SNAP91. Experimentally altered expression of three of them, FURIN, 81 TSNARE1, and CNTN4, perturbs the proliferation and apoptotic index of neural progenitors and 82 leads to neuroanatomical deficits in zebrafish. Furthermore, shRNA mediated knock-down of 83 FURIN in neural progenitor cells derived from human induced pluripotent stem cells produces 84 abnormal neural migration. Although 4.2% of genes (N = 693) display significant differential 85 expression between cases and controls, 44% show some evidence for differential expression. 86All fold changes are ≤ 1.33, and an independent cohort yields similar differential expression for 87 these 693 genes (r = 0.58). These findings are consistent with schizophrenia being highly 88 polygenic, as has been reported in investigations of common and rare genetic variation. Co-89 expression analyses identify a gene module that shows enrichment for genetic associations and 90 is thus relevant for schizophrenia. Taken together, these results pave the way for mechanistic 91 interpretations of genetic liability for schizophrenia and other brain diseases. 4The human brain is complicated and not well understood. Seemingly straightforward 93 fundamental information such as which genes are expressed therein and what functions they 94 perform are only partially characterized. To overcome these obstacles, we established the 95 CommonMind Consortium (CMC; www.synpase.org/CMC), a public-private partnership to 96 generate functional genomic data in brain samples obtained from autopsies of cases with and 97 without severe psychiatric disorders. The CMC is the largest existing collection of collaborating 98 brain banks and includes over 1,150 samples. A wide spectrum of data is being generated on 99 these samples including regional gene expression, epigenomics (cell-type specific histone 100 modifications and open chromatin), whole genome sequencing, and somatic mosaicism. 101 102 Schizophrenia (SCZ), affecting roughly 0.7% of adults, is a severe psychiatric disorder 103 characterized by abnormalities in thought and cognition (1). Despite a century of evidence 104 establishing its genetic basis, only recently have specific genetic risk factors been conclusively 105identified, including rare copy number variants (2) and >100 common variants (3). However, 106 there is not a one-to-one Mendelian mapping between these SCZ ris...

Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4-PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.

Eleven studies now report significant associations between schizophrenia and certain haplotypes of singlenucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73-93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18-42% (P = 0.027-0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., β-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.

To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type–specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type–specific disease risk vulnerabilities in spatial genome organization.

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