Summary Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here, we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose mRNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.

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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 schizophrenia cases (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 changes neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yields abnormal migration. Of 693 genes showing significant case/control differential expression, their fold changes are ≤ 1.33, and an independent cohort yields similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics, and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads, and prioritize genes for functional follow-up studies.

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...