Elucidating brain cell type specific gene expression patterns is critical towards a better understanding of how cell-cell communications may influence brain functions and dysfunctions. We set out to ...compare and contrast five human and murine cell type-specific transcriptome-wide RNA expression data sets that were generated within the past several years. We defined three measures of brain cell type-relative expression including specificity, enrichment, and absolute expression and identified corresponding consensus brain cell "signatures," which were well conserved across data sets. We validated that the relative expression of top cell type markers are associated with proxies for cell type proportions in bulk RNA expression data from postmortem human brain samples. We further validated novel marker genes using an orthogonal ATAC-seq dataset. We performed multiscale coexpression network analysis of the single cell data sets and identified robust cell-specific gene modules. To facilitate the use of the cell type-specific genes for cell type proportion estimation and deconvolution from bulk brain gene expression data, we developed an R package, BRETIGEA. In summary, we identified a set of novel brain cell consensus signatures and robust networks from the integration of multiple datasets and therefore transcend limitations related to technical issues characteristic of each individual study.
Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely ...unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.
SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell-autonomous effects of SARS-CoV-2 infection is ...imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters, SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (ORs) and of their signaling components. This non-cell-autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.
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•Downregulation of odor detection pathways may explain COVID-19-induced anosmia•SARS-CoV-2-mediated disruption of nuclear architecture may impair odor detection•SARS-CoV-2-mediated nuclear reorganization is non-cell autonomous
SARS-CoV-2 induces non-cell-autonomous effects in olfactory epithelium that disrupts nuclear architecture and downregulates olfactory receptor expression in olfactory sensory neurons.
Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. ...To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in the brain are highly enriched for schizophrenia SNP heritability. Accessible chromatin regions that overlap evolutionarily conserved regions exhibit an even higher heritability enrichment, indicating that sequence conservation can further refine functional risk variants. We identify few differences in chromatin accessibility between cases and controls, in contrast to thousands of age-related differential accessible chromatin regions. Altogether, we characterize chromatin accessibility in the human prefrontal cortex, the effect of schizophrenia and age on chromatin accessibility, and provide evidence that our dataset will allow for fine mapping of risk variants.
Transcriptome-wide association studies integrate gene expression data with common risk variation to identify gene-trait associations. By incorporating epigenome data to estimate the functional ...importance of genetic variation on gene expression, we generate a small but significant improvement in the accuracy of transcriptome prediction and increase the power to detect significant expression-trait associations. Joint analysis of 14 large-scale transcriptome datasets and 58 traits identify 13,724 significant expression-trait associations that converge on biological processes and relevant phenotypes in human and mouse phenotype databases. We perform drug repurposing analysis and identify compounds that mimic, or reverse, trait-specific changes. We identify genes that exhibit agonistic pleiotropy for genetically correlated traits that converge on shared biological pathways and elucidate distinct processes in disease etiopathogenesis. Overall, this comprehensive analysis provides insight into the specificity and convergence of gene expression on susceptibility to complex traits.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been associated with neurological and neuropsychiatric illness in many ...individuals. We sought to further our understanding of the relationship between brain tropism, neuro-inflammation, and host immune response in acute COVID-19 cases.
Three brain regions (dorsolateral prefrontal cortex, medulla oblongata, and choroid plexus) from 5 patients with severe COVID-19 and 4 controls were examined. The presence of the virus was assessed by western blot against viral spike protein, as well as viral transcriptome analysis covering > 99% of SARS-CoV-2 genome and all potential serotypes. Droplet-based single-nucleus RNA sequencing (snRNA-seq) was performed in the same samples to examine the impact of COVID-19 on transcription in individual cells of the brain.
Quantification of viral spike S1 protein and viral transcripts did not detect SARS-CoV-2 in the postmortem brain tissue. However, analysis of 68,557 single-nucleus transcriptomes from three distinct regions of the brain identified an increased proportion of stromal cells, monocytes, and macrophages in the choroid plexus of COVID-19 patients. Furthermore, differential gene expression, pseudo-temporal trajectory, and gene regulatory network analyses revealed transcriptional changes in the cortical microglia associated with a range of biological processes, including cellular activation, mobility, and phagocytosis.
Despite the absence of detectable SARS-CoV-2 in the brain at the time of death, the findings suggest significant and persistent neuroinflammation in patients with acute COVID-19.
Most common genetic risk variants associated with neuropsychiatric disease are noncoding and are thought to exert their effects by disrupting the function of
regulatory elements (CREs), including ...promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further understand the complex mechanisms that modulate transcription in the brain, we used frozen postmortem samples to generate the largest human brain and cell-type-specific open chromatin data set to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in two cell types (neurons and non-neurons) across 14 distinct brain regions of five individuals. Chromatin structure varies markedly by cell type, with neuronal chromatin displaying higher regional variability than that of non-neurons. Among our findings is an open chromatin region (OCR) specific to neurons of the striatum. When placed in the mouse, a human sequence derived from this OCR recapitulates the cell type and regional expression pattern predicted by our ATAC-seq experiments. Furthermore, differentially accessible chromatin overlaps with the genetic architecture of neuropsychiatric traits and identifies differences in molecular pathways and biological functions. By leveraging transcription factor binding analysis, we identify protein-coding and long noncoding RNAs (lncRNAs) with cell-type and brain region specificity. Our data provide a valuable resource to the research community and we provide this human brain chromatin accessibility atlas as an online database "Brain Open Chromatin Atlas (BOCA)" to facilitate interpretation.
While large-scale, genome-wide association studies (GWAS) have identified hundreds of loci associated with brain-related traits, identification of the variants, genes and molecular mechanisms ...underlying these traits remains challenging. Integration of GWAS with expression quantitative trait loci (eQTLs) and identification of shared genetic architecture have been widely adopted to nominate genes and candidate causal variants. However, this approach is limited by sample size, statistical power and linkage disequilibrium. We developed the multivariate multiple QTL approach and performed a large-scale, multi-ancestry eQTL meta-analysis to increase power and fine-mapping resolution. Analysis of 3,983 RNA-sequenced samples from 2,119 donors, including 474 non-European individuals, yielded an effective sample size of 3,154. Joint statistical fine-mapping of eQTL and GWAS identified 329 variant-trait pairs for 24 brain-related traits driven by 204 unique candidate causal variants for 189 unique genes. This integrative analysis identifies candidate causal variants and elucidates potential regulatory mechanisms for genes underlying schizophrenia, bipolar disorder and Alzheimer's disease.
Microglia are brain myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimer's disease (AD), yet our understanding of how the genetic regulatory landscape controls ...microglial function and contributes to AD is limited. Here, we performed transcriptome and chromatin accessibility profiling in primary human microglia from 150 donors to identify genetically driven variation and cell-specific enhancer-promoter (E-P) interactions. Integrative fine-mapping analysis identified putative regulatory mechanisms for 21 AD risk loci, of which 18 were refined to a single gene, including 3 new candidate risk genes (KCNN4, FIBP and LRRC25). Transcription factor regulatory networks captured AD risk variation and identified SPI1 as a key putative regulator of microglia expression and AD risk. This comprehensive resource capturing variation in the human microglia regulome provides insights into the etiology of neurodegenerative disease.
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•Genetic Diversity Unveiled: ‘Omics’ studies uncover SCZ’s polygenic nature, revealing both common and rare variants.•Cellular Complexity Unveiled: Single-cell scrutiny is essential ...to dissecting the role of SNPs in specific cell types and unlocking SCZ’s complexity.•Epigenetic Symphony in SCZ: Diverse epigenomic mechanisms guide the brain’s dynamic plasticity in SCZ pathogenesis.•Glutamatergic Signaling and Synaptic plasticity: These processes guide neuronal morphology and underpin SCZ’s core pathology.•Measuring Expression with Precision: RNA-seq, ATAC-seq, Hi-C and Multiomic assays have helped to unravel SCZ’s genetic secrets.
Neuronal development is a highly regulated mechanism that is central to organismal function in animals. In humans, disruptions to this process can lead to a range of neurodevelopmental phenotypes, including Schizophrenia (SCZ). SCZ has a significant genetic component, whereby an individual with an SCZ affected family member is eight times more likely to develop the disease than someone with no family history of SCZ. By examining a combination of genomic, transcriptomic and epigenomic datasets, large-scale ‘omics’ studies aim to delineate the relationship between genetic variation and abnormal cellular activity in the SCZ brain. Herein, we provide a brief overview of some of the key omics methods currently being used in SCZ research, including RNA-seq, the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and high-throughput chromosome conformation capture (3C) approaches (e.g., Hi-C), as well as single-cell/nuclei iterations of these methods. We also discuss how these techniques are being employed to further our understanding of the genetic basis of SCZ, and to identify associated molecular pathways, biomarkers, and candidate drug targets.
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