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Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas. Thousands of significant histone quantitative trait loci were identified in neuronal and neuron-depleted samples. Risk variants for schizophrenia, depressive symptoms and neuroticism were significantly over-represented in neuronal H3K4me3 and H3K27ac landscapes. Our Resource, sponsored by PsychENCODE and CommonMind, highlights the critical role of cell-type-specific signatures at regulatory and disease-associated noncoding sequences in the human frontal lobe.

Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) ( n  = 739). We mapped thousands of cis -regulatory domains (CRDs), revealing fine-grained, 10 4 –10 6 -bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains. Girdhar et al. constructed chromosomal domains from prefrontal histone acetylation and methylation maps and discovered, in a large cohort of schizophrenia and bipolar brains, converging alignment by genetic risk, neuronal function and three-dimensional genomics.

Structural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs. Structural variants (SVs) contribute to the genetic architecture of many brain-related disorders. Here, the authors integrate SV calls from genome sequencing (n = 755) with RNA-seq data (n = 629) from post-mortem dorsal lateral prefrontal cortex to annotate the gene regulatory effects of SVs in the human brain and their potential to contribute to disease.

Pulmonary embolism is a life-threatening medical emergency associated with right ventricular failure. Rarely, it impacts the left ventricle to the point of compromising the left ventricular (LV) ejection fraction. We present a case of a 73-year-old African American male with a medical history pertinent for intravascular large B-cell lymphoma who developed an acute saddle embolus with a “clot-in-transit” and profound LV systolic dysfunction. Our report illustrates how an acute saddle embolus may be associated with LV systolic dysfunction via the “reverse Bernheim effect.” Additionally, the report highlights the significance of a “clot-in-transit” and LV systolic dysfunction, as they both directly correlate with increased risk of mortality.

RNA editing critically regulates neurodevelopment and normal neuronal function. The global landscape of RNA editing was surveyed across 364 schizophrenia cases and 383 control postmortem brain samples from the CommonMind Consortium, comprising two regions: dorsolateral prefrontal cortex and anterior cingulate cortex. In schizophrenia, RNA editing sites in genes encoding AMPA-type glutamate receptors and postsynaptic density proteins were less edited, whereas those encoding translation initiation machinery were edited more. These sites replicate between brain regions, map to 3′-untranslated regions and intronic regions, share common sequence motifs and overlap with binding sites for RNA-binding proteins crucial for neurodevelopment. These findings cross-validate in hundreds of non-overlapping dorsolateral prefrontal cortex samples. Furthermore, ~30% of RNA editing sites associate with cis-regulatory variants (editing quantitative trait loci or edQTLs). Fine-mapping edQTLs with schizophrenia risk loci revealed co-localization of eleven edQTLs with six loci. The findings demonstrate widespread altered RNA editing in schizophrenia and its genetic regulation, and suggest a causal and mechanistic role of RNA editing in schizophrenia neuropathology.

Abstract Background Genomic dysregulation is likely to contribute to neuronal dysfunction in prefrontal cortex (PFC) and other brain regions affected in schizophrenia (SCZ), but genome-scale mapping of neuronal transcriptomes and epigenomes has not been conducted in larger cohorts. We have shown recently that the genomic landscape of open chromatin-associated histone modifications, including histone H3-acetyl-lysine 27 (H3K27ac), show in neurons significant associations with the genetic risk architecture of schizophrenia. Methods We conducted H3K4me3 (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) on fluorescence-activated cell sorted (FACS) nuclei from dorsolateral PFC of 250 postmortem samples from SCZ and 280 matched control brains, generating altogether ~7(11) billion reads representing H3K4me3 (H3K27ac)-tagged nucleosomal DNA from PFC neurons. In addition, genotyping for the entire cohort of 530 brains was performed. Results Enrichment of differentially modified regions across schizophrenia cases and controls in calcium and potassium signaling pathways. This finding was replicated in differentially modified regions across cases and controls obtained from independent cohort. In addition to this, enrichment of schizophrenia GWAS loci was observed in differentially modified regions across cases and controls. Discussion Our dataset will provide unique insights into non-coding variants associated with neuronal dysfunction in schizophrenia. Our PsychENCODE sponsored resource highlights the critical role of cell-type specific signatures at regulatory and disease-associated non-coding sequences in the human frontal lobe. This is the first histone methylation and acetylation ChIP-seq datasets generated from prefrontal cortex brain region of 250 schizophrenia cases and 280 controls, postmortem human brain samples. As of now, this is the largest, yet unpublished ChIP-seq dataset from schizophrenia and control brains.

To explore modular organization of chromosomes in schizophrenia (SCZ) and bipolar disorder (BD), we applied ‘population-scale’ correlational structuring of 739 histone H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from the prefrontal cortex (PFC) of 568 cases and controls. Neuronal histone acetylomes and methylomes assembled as thousands of cis-regulatory domains (CRDs), revealing fine-grained, kilo-to megabase scale chromatin organization at higher resolution but firmly integrated into Hi-C chromosomal conformations. Large clusters of domains that were hyperacetylated in disease shared spatial positioning within the nucleus, predominantly regulating PFC projection neuron function and excitatory neurotransmission. Hypoacetylated domains were linked to inhibitory interneuron- and myelination-relevant genes. Chromosomal modular architecture is affected in SCZ and BD, with hyperacetylated domains showing unexpectedly strong convergences defined by cell type, nuclear topography, genetic risk, and active chromatin state across a wide developmental window.