James A. Knowles

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

INTRODUCTION Strong genetic associations have been found for a number of psychiatric disorders. However, understanding the underlying molecular mechanisms remains challenging. RATIONALE To address this challenge, the PsychENCODE Consortium has developed a comprehensive online resource and integrative models for the functional genomics of the human brain. RESULTS The base of the pyramidal resource is the datasets generated by PsychENCODE, including bulk transcriptome, chromatin, genotype, and Hi-C datasets and single-cell transcriptomic data from ~32,000 cells for major brain regions. We have merged these with data from Genotype-Tissue Expression (GTEx), ENCODE, Roadmap Epigenomics, and single-cell analyses. Via uniform processing, we created a harmonized resource, allowing us to survey functional genomics data on the brain over a sample size of 1866 individuals. From this uniformly processed dataset, we created derived data products. These include lists of brain-expressed genes, coexpression modules, and single-cell expression profiles for many brain cell types; ~79,000 brain-active enhancers with associated Hi-C loops and topologically associating domains; and ~2.5 million expression quantitative-trait loci (QTLs) comprising ~238,000 linkage-disequilibrium–independent single-nucleotide polymorphisms and of other types of QTLs associated with splice isoforms, cell fractions, and chromatin activity. By using these, we found that >88% of the cross-population variation in brain gene expression can be accounted for by cell fraction changes. Furthermore, a number of disorders and aging are associated with changes in cell-type proportions. The derived data also enable comparison between the brain and other tissues. In particular, by using spectral analyses, we found that the brain has distinct expression and epigenetic patterns, including a greater extent of noncoding transcription than other tissues. The top level of the resource consists of integrative networks for regulation and machine-learning models for disease prediction. The networks include a full gene regulatory network (GRN) for the brain, linking transcription factors, enhancers, and target genes from merging of the QTLs, generalized element-activity correlations, and Hi-C data. By using this network, we link disease genes to genome-wide association study (GWAS) variants for psychiatric disorders. For schizophrenia, we linked 321 genes to the 142 reported GWAS loci. We then embedded the regulatory network into a deep-learning model to predict psychiatric phenotypes from genotype and expression. Our model gives a ~6-fold improvement in prediction over additive polygenic risk scores. Moreover, it achieves a ~3-fold improvement over additive models, even when the gene expression data are imputed, highlighting the value of having just a small amount of transcriptome data for disease prediction. Lastly, it highlights key genes and pathways associated with disorder prediction, including immunological, synaptic, and metabolic pathways, recapitulating de novo results from more targeted analyses. CONCLUSION Our resource and integrative analyses have uncovered genomic elements and networks in the brain, which in turn have provided insight into the molecular mechanisms underlying psychiatric disorders. Our deep-learning model improves disease risk prediction over traditional approaches and can be extended with additional data types (e.g., microRNA and neuroimaging). A comprehensive functional genomic resource for the adult human brain. The resource forms a three-layer pyramid. The bottom layer includes sequencing datasets for traits, such as schizophrenia. The middle layer represents derived datasets, including functional genomic elements and QTLs. The top layer contains integrated models, which link genotypes to phenotypes. DSPN, Deep Structured Phenotype Network; PC1 and PC2, principal components 1 and 2; ref, reference; alt, alternate; H3K27ac, histone H3 acetylation at lysine 27.

INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders. RATIONALE The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain. RESULTS Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes including MEF2C , SATB2 , and TCF4 , with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity. CONCLUSION We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease. Spatiotemporal dynamics of human brain development and neuropsychiatric risks. Human brain development begins during embryonic development and continues through adulthood (top). Integrating data modalities (bottom left) revealed age- and cell type–specific properties and global patterns of transcriptional dynamics, including a late fetal transition (bottom middle). We related the variation in gene expression (brown, high; purple, low) to regulatory elements in the fetal and adult brains, cell type–specific signatures, and genetic loci associated with neuropsychiatric disorders (bottom right; gray circles indicate enrichment for corresponding features among module genes). Relationships depicted in this panel do not correspond to specific observations. CBC, cerebellar cortex; STR, striatum; HIP, hippocampus; MD, mediodorsal nucleus of thalamus; AMY, amygdala.