Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in disease brain are limited. Here, we integrate genotype and RNA-sequencing in brain samples from 1695 subjects with autism, schizophrenia, bipolar disorder and controls. Over 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. co-expression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon response modules defining novel neural-immune mechanisms. We prioritize disease loci likely mediated by cis-effects on brain expression via transcriptome-wide association analysis. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer’s disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.

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The primary antigenic and virulence determinant of the human malaria parasite Plasmodium falciparum is a variant surface protein called PfEMP1. Different forms of PfEMP1 are encoded by a multicopy gene family called var , and switching between active genes enables the parasites to evade the antibody response of their human hosts. var gene switching is key for the maintenance of chronic infections; however, what controls switching is unknown, although it has been suggested to occur at a constant frequency with little or no environmental influence. var gene transcription is controlled epigenetically through the activity of histone methyltransferases (HMTs). Studies in model systems have shown that metabolism and epigenetic control of gene expression are linked through the availability of intracellular S-adenosylmethionine (SAM), the principal methyl donor in biological methylation modifications, which can fluctuate based on nutrient availability. To determine whether environmental conditions and changes in metabolism can influence var gene expression, P . falciparum was cultured in media with altered concentrations of nutrients involved in SAM metabolism. We found that conditions that influence lipid metabolism induce var gene switching, indicating that parasites can respond to changes in their environment by altering var gene expression patterns. Genetic modifications that directly modified expression of the enzymes that control SAM levels similarly led to profound changes in var gene expression, confirming that changes in SAM availability modulate var gene switching. These observations directly challenge the paradigm that antigenic variation in P. falciparum follows an intrinsic, programed switching rate, which operates independently of any external stimuli.

T he brain, our most complex organ, is at the root of both the cognitive and behavioral repertoires that make us unique as a species and underlies susceptibility to neuropsychiatric disorders. Healthy brain development and neurological function rely on precise spatiotemporal regulation of the transcriptome, which varies substantially by brain region and cell type. Recent advances in the genetics of neuropsychiatric disorders reveal a highly polygenic risk architecture involving contributions of multiple common variants with small ef ects and rare variants with a range of ef ects. Because most of this genetic variation resides in noncoding regions of the genome, establishment of mechanistic links between variants and disease phenotypes is impeded by a lack of a comprehensive understanding of the regulatory and epigenomic landscape of the human brain.To address this matter, the PsychENCODE Consortium was established in 2015 by the National Institute of Mental Health (NIMH) to characterize the full spectrum of genomic elements active within the human brain and to elucidate their roles in development, evolution, and neuropsychiatric disorders. To reach this objective, a multidisciplinary team of investigators across 15 research institutes has generated an integrative atlas of the human brain by analyzing transcriptomic, epigenomic, and genomic data of postmortem adult and developing human brains at both the tissue and single-cell levels. Samples from more than 2000 individuals were phenotypically characterized as neurotypical or diagnosed with schizophrenia, autism spectrum disorder (ASD), or bipolar disorder.In Science, Science Translational Medicine, and Science Advances, we present manuscripts that provide insights into the biology of the developing, adult, and diseased human brain. These papers are organized around three fl agship articles, the fi rst analyzing human development, the second examining disease transcriptomes, and the third describing integration of tissue and single-cell data with deep-learning approaches.The consortium's integrative genomic analyses elucidate the mechanisms by which cellular diversity and patterns of gene