Previous investigations have combined transcriptional and genetic analyses in human cell lines1-3, but few have applied these techniques to human neural tissue4-8. To gain a global molecular perspective on the role of the human genome in cortical development, function and ageing, we explore the temporal dynamics and genetic control of transcription in human prefrontal cortex in an extensive series of post-mortem brains from fetal development through ageing. We discover a wave of gene expression changes occurring during fetal development which are reversed in early postnatal life. One half-century later in life, this pattern of reversals is mirrored in ageing and in neurodegeneration. Although we identify thousands of robust associations of individual genetic polymorphisms with gene expression, we also demonstrate that there is no association between the total extent of genetic differences between subjects and the global similarity of their transcriptional profiles. Hence, the human genome produces a consistent molecular architecture in the prefrontal cortex, despite millions of genetic differences across individuals and races. To enable further discovery, this entire data set is freely available (from Gene Expression Omnibus: accession GSE30272; and dbGaP: accession phs000417.v1.p1) and can also be interrogated via a biologist-friendly stand-alone application (http://www.libd.org/braincloud).

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry 1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific 4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may Reprints and permissions information is available at http://www.nature.com/reprints.

DNA methylation (DNAm) is important in brain development, and potentially in schizophrenia. We characterized DNAm in prefrontal cortex from 335 non-psychiatric controls across the lifespan and 191 patients with schizophrenia, and identified widespread changes in the transition from prenatal to postnatal life. These DNAm changes manifest in the transcriptome, correlate strongly with a shifting cellular landscape, and overlap regions of genetic risk for schizophrenia. A quarter of published GWAS-suggestive loci (4,208/15,930, p<10−100) manifest as significant methylation quantitative trait loci (meQTLs), including 59.6% of GWAS-positive schizophrenia loci. We identified 2,104 CpGs that differ between schizophrenia patients and controls, enriched for genes related to development and neurodifferentiation. The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS risk loci, while not corresponding to CpGs differentiating adolescence from later adult life. These data implicate an epigenetic component to the developmental origins of this disorder.

Genome-wide association studies have identified 108 schizophrenia risk loci, but biological mechanisms for individual loci are largely unknown. Using developmental, genetic and illness-based RNA sequencing expression analysis in human brain, we characterized the human brain transcriptome around these loci and found enrichment for developmentally regulated genes with novel examples of shifting isoform usage across pre- and postnatal life. We found widespread expression quantitative trait loci (eQTLs), including many with transcript specificity and previously unannotated sequence that were independently replicated. We leveraged this general eQTL database to show that 48.1% of risk variants for schizophrenia associate with nearby expression. We lastly found 237 genes significantly differentially expressed between patients and controls, which replicated in an independent dataset, implicated synaptic processes, and were strongly regulated in early development. These findings together offer genetics- and diagnosis-related targets for better modeling of schizophrenia risk. This resource is publicly available at http://eqtl.brainseq.org/phase1 .

The human prefrontal cortex (PFC), a mastermind of the brain, is one of the last brain regions to mature. To investigate the role of epigenetics in the development of PFC, we examined DNA methylation in ∼14,500 genes at ∼27,000 CpG loci focused on 5' promoter regions in 108 subjects range in age from fetal to elderly. DNA methylation in the PFC shows unique temporal patterns across life. The fastest changes occur during the prenatal period, slow down markedly after birth and continue to slow further with aging. At the genome level, the transition from fetal to postnatal life is typified by a reversal of direction, from demethylation prenatally to increased methylation postnatally. DNA methylation is strongly associated with genotypic variants and correlates with expression of a subset of genes, including genes involved in brain development and in de novo DNA methylation. Our results indicate that promoter DNA methylation in the human PFC is a highly dynamic process modified by genetic variance and regulating gene transcription. Additional discovery is made possible with a stand-alone application, BrainCloudMethyl.

Highlights d Dorsolateral prefrontal cortex and hippocampus gene expression across development d Novel region-specific schizophrenia genetic risk features d Decreased regional functional coherence in schizophrenia d Public brain gene expression and eQTL resource at http:// eqtl.brainseq.org/phase2

SUMMARY Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MYC-driven MB has a particularly poor prognosis, and would greatly benefit from more effective therapies. We used an animal model of MYC-driven MB to screen for drugs that decrease viability of tumor cells. Among the most effective compounds were histone deacetylase inhibitors (HDACI). HDACI potently inhibit survival of MYC-driven MB cells in vitro, in part by inducing expression of the FOXO1 tumor suppressor gene. HDACI also synergize with phosphatidylinositol 3-kinase inhibitors (PI3KI) to inhibit tumor growth in vivo. These studies identify an effective combination therapy for the most aggressive form of MB.

RNA editing is increasingly recognized as a molecular mechanism regulating RNA activity and recoding proteins. Here we surveyed the global landscape of RNA editing in human brain tissues and identified three unique patterns of A-to-I RNA editing rates during cortical development: stable high, stable low and increasing. RNA secondary structure and the temporal expression of adenosine deaminase acting on RNA (ADAR) contribute to cis- and trans-regulatory mechanisms of these RNA editing patterns, respectively. Interestingly, the increasing pattern was associated with neuronal maturation, correlated with mRNA abundance and potentially influenced miRNA binding energy. Gene ontology analyses implicated the increasing pattern in vesicle or organelle membrane-related genes and glutamate signaling pathways. We also found that the increasing pattern was selectively perturbed in spinal cord injury and glioblastoma. Our findings reveal global and dynamic aspects of RNA editing in brain, providing new insight into epitranscriptional regulation of sequence diversity.