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2.
bioRxiv ; 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-39026764

RESUMO

Background: Individuals with cocaine use disorder (CUD) who attempt abstinence experience craving and relapse, which poses challenges in treatment. Longitudinal studies linking behavioral manifestations in CUD to the blood transcriptome in living individuals are limited. Therefore, we investigated the connection between drug use behaviors during abstinence with blood transcriptomics. Methods: We conducted a comprehensive longitudinal study involving 12 subjects (9 males, 3 females) with CUD and RNA sequencing on blood collected at a drug-free baseline, and 3, 6 & 9 months thereafter. We categorized subjects into 2 responder groups (high-low) based on scores of drug use variables, and 3 responder groups (low-intermediate-high) on days of abstinence. We investigated differential expression and gene-transcript associations across responder groups at each time point. Lastly, we examined genes that are both co-expressed and showed dynamic expression with time. Results: Genes with significant transcript associations between high and. intermediate days of abstinence at 9 months were notably enriched for cannabis use disorder, drinks weekly, and coronary artery disease risk genes. Time-specific gene co-expression analysis prioritized transcripts related to immune processes, cell cycle, RNA-protein synthesis, and second messenger signaling for days of abstinence. Conclusion: We demonstrate that abstinence reflects robust changes in drug use behaviors and the blood transcriptome in CUD. We also highlight the importance of longitudinal studies to capture complex biological processes during abstinence in CUD.

3.
Nat Commun ; 15(1): 5366, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38926387

RESUMO

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.


Assuntos
Adenosina Desaminase , Adenosina , Autopsia , Encéfalo , Inosina , Edição de RNA , Proteínas de Ligação a RNA , Humanos , Adenosina/metabolismo , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Encéfalo/metabolismo , Inosina/metabolismo , Inosina/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Córtex Pré-Frontal/metabolismo , Mudanças Depois da Morte , Masculino
4.
medRxiv ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38765961

RESUMO

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR1 and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.

5.
Science ; 384(6698): eadi5199, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38781369

RESUMO

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.


Assuntos
Encéfalo , Redes Reguladoras de Genes , Transtornos Mentais , Análise de Célula Única , Humanos , Envelhecimento/genética , Encéfalo/metabolismo , Comunicação Celular/genética , Cromatina/metabolismo , Cromatina/genética , Genômica , Transtornos Mentais/genética , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Locos de Características Quantitativas
6.
Science ; 384(6698): eadg5136, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38781388

RESUMO

The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation and the development of more effective therapies. Here, we performed single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across 140 individuals in two independent cohorts. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Transcriptional alterations included known genetic risk factors, suggesting convergence of rare and common genomic variants on neuronal population-specific alterations in schizophrenia. Based on the magnitude of schizophrenia-associated transcriptional change, we identified two populations of individuals with schizophrenia marked by expression of specific excitatory and inhibitory neuronal cell states. This single-cell atlas links transcriptomic changes to etiological genetic risk factors, contextualizing established knowledge within the human cortical cytoarchitecture and facilitating mechanistic understanding of schizophrenia pathophysiology and heterogeneity.


Assuntos
Predisposição Genética para Doença , Neuroglia , Neurônios , Córtex Pré-Frontal , Esquizofrenia , Análise de Célula Única , Adulto , Feminino , Humanos , Masculino , Estudos de Coortes , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Fatores de Risco , Esquizofrenia/genética , Sinapses/metabolismo , Transcriptoma , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neuroglia/metabolismo
7.
Sci Adv ; 10(21): eadh2588, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38781336

RESUMO

Sample-wise deconvolution methods estimate cell-type proportions and gene expressions in bulk tissue samples, yet their performance and biological applications remain unexplored, particularly in human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk tissue RNA sequencing (RNA-seq), single-cell/nuclei (sc/sn) RNA-seq, and immunohistochemistry. A total of 1,130,767 nuclei per cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expressions. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The results showed that decon-eQTLs explained more schizophrenia GWAS heritability than bulk tissue or single-cell eQTLs did alone. Differential gene expressions associated with Alzheimer's disease, schizophrenia, and brain development were also examined using the deconvoluted data. Our findings, which were replicated in bulk tissue and single-cell data, provided insights into the biological applications of deconvoluted data in multiple brain disorders.


Assuntos
Encéfalo , Análise de Célula Única , Transcriptoma , Humanos , Encéfalo/metabolismo , Análise de Célula Única/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Perfilação da Expressão Gênica/métodos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Estudo de Associação Genômica Ampla/métodos , Análise de Sequência de RNA/métodos , Adulto
8.
Trends Mol Med ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38821772

RESUMO

Neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD) constitute multifaceted behavioral manifestations that reflect processes of emotional regulation, thinking, and social behavior. They are as prevalent in AD as cognitive impairment and develop independently during the progression of neurodegeneration. As studying NPSs in AD is clinically challenging, most AD research to date has focused on cognitive decline. In this opinion article we summarize emerging literature on the prevalence, time course, and the underlying genetic, molecular, and pathological mechanisms related to NPSs in AD. Overall, we propose that NPSs constitute a cluster of core symptoms in AD, and understanding their neurobiology can lead to a more holistic approach to AD research, paving the way for more accurate diagnostic tests and personalized treatments embracing the goals of precision medicine.

9.
Science ; 384(6698): eadh4265, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38781378

RESUMO

Nucleotide variants in cell type-specific gene regulatory elements in the human brain are risk factors for human disease. We measured chromatin accessibility in 1932 aliquots of sorted neurons and non-neurons from 616 human postmortem brains and identified 34,539 open chromatin regions with chromatin accessibility quantitative trait loci (caQTLs). Only 10.4% of caQTLs are shared between neurons and non-neurons, which supports cell type-specific genetic regulation of the brain regulome. Incorporating allele-specific chromatin accessibility improves statistical fine-mapping and refines molecular mechanisms that underlie disease risk. Using massively parallel reporter assays in induced excitatory neurons, we screened 19,893 brain QTLs and identified the functional impact of 476 regulatory variants. Combined, this comprehensive resource captures variation in the human brain regulome and provides insights into disease etiology.


Assuntos
Encefalopatias , Encéfalo , Cromatina , Regulação da Expressão Gênica , Elementos Reguladores de Transcrição , Humanos , Alelos , Encéfalo/metabolismo , Encefalopatias/genética , Cromatina/metabolismo , Neurônios/metabolismo , Locos de Características Quantitativas , Masculino , Feminino
10.
bioRxiv ; 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38562822

RESUMO

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

11.
Res Sq ; 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38645177

RESUMO

Our understanding of the sex-specific role of the non-coding genome in serious mental illness remains largely incomplete. To address this gap, we explored sex differences in 1,393 chromatin accessibility profiles, derived from neuronal and non-neuronal nuclei of two distinct cortical regions from 234 cases with serious mental illness and 235 controls. We identified sex-specific enhancer-promoter interactions and showed that they regulate genes involved in X-chromosome inactivation (XCI). Examining chromosomal conformation allowed us to identify sex-specific cis- and trans-regulatory domains (CRDs and TRDs). Co-localization of sex-specific TRDs with schizophrenia common risk variants pinpointed male-specific regulatory regions controlling a number of metabolic pathways. Additionally, enhancers from female-specific TRDs were found to regulate two genes known to escape XCI, (XIST and JPX), underlying the importance of TRDs in deciphering sex differences in schizophrenia. Overall, these findings provide extensive characterization of sex differences in the brain epigenome and disease-associated regulomes.

12.
Res Sq ; 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38343831

RESUMO

Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer's Disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood. Here, we present the transcriptional landscape of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, including 63 patients representing the full spectrum of clinical and pathological severity of AD. We identified transcriptional changes associated with multiple AD phenotypes, capturing the severity of dementia and neuropathological lesions. Transcript-level analyses identified additional genes with heterogeneous isoform usage and AD phenotypes. We identified changes in gene-gene coordination in AD, dysregulation of co-expression modules, and disease subtypes with distinct gene expression. Taken together, these data further our understanding of the key role of microglia in AD biology and nominate candidates for therapeutic intervention.

13.
Gene ; 902: 148198, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38266791

RESUMO

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.


Assuntos
Esquizofrenia , Animais , Humanos , Esquizofrenia/genética , Cromatina/genética , Cromatina/metabolismo , Sequenciamento de Cromatina por Imunoprecipitação , Encéfalo/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala
14.
Mol Psychiatry ; 29(3): 782-792, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38145985

RESUMO

Enhancers play an essential role in the etiology of schizophrenia; however, the dysregulation of enhancer activity and its impact on the regulome in schizophrenia remains understudied. To address this gap in our knowledge, we assessed enhancer and gene expression in 1,382 brain samples comprising cases with schizophrenia and unaffected controls. Dysregulation of enhancer expression was concordant with changes in gene expression, and was more closely associated with schizophrenia polygenic risk, suggesting that enhancer dysregulation is proximal to the genetic etiology of the disease. Modeling the shared variance of cis-coordinated genes and enhancers revealed a gene regulatory program that was highly associated with genetic vulnerability to schizophrenia. By integrating coordinated factors with evolutionary constraints, we found that enhancers acquired during human evolution are more likely to regulate genes that are implicated in neuropsychiatric disorders and, thus, hold potential as therapeutic targets. Our analysis provides a systematic view of regulome dysregulation in schizophrenia and highlights its convergence with schizophrenia polygenic risk and human-gained enhancers.


Assuntos
Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Herança Multifatorial , Esquizofrenia , Humanos , Esquizofrenia/genética , Herança Multifatorial/genética , Predisposição Genética para Doença/genética , Elementos Facilitadores Genéticos/genética , Masculino , Feminino , Estudo de Associação Genômica Ampla/métodos , Encéfalo/metabolismo , Regulação da Expressão Gênica/genética , Fatores de Risco , Polimorfismo de Nucleotídeo Único/genética , Adulto
15.
Biol Psychiatry ; 95(2): 187-198, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-37454787

RESUMO

BACKGROUND: Converging evidence from large-scale genetic and postmortem studies highlights the role of aberrant neurotransmission and genetic regulation in brain-related disorders. However, identifying neuronal activity-regulated transcriptional programs in the human brain and understanding how changes contribute to disease remain challenging. METHODS: To better understand how the activity-dependent regulome contributes to risk for brain-related disorders, we profiled the transcriptomic and epigenomic changes following neuronal depolarization in human induced pluripotent stem cell-derived glutamatergic neurons (NGN2) from 6 patients with schizophrenia and 5 control participants. RESULTS: Multiomic data integration associated global patterns of chromatin accessibility with gene expression and identified enhancer-promoter interactions in glutamatergic neurons. Within 1 hour of potassium chloride-induced depolarization, independent of diagnosis, glutamatergic neurons displayed substantial activity-dependent changes in the expression of genes regulating synaptic function. Depolarization-induced changes in the regulome revealed significant heritability enrichment for schizophrenia and Parkinson's disease, adding to mounting evidence that sequence variation within activation-dependent regulatory elements contributes to the genetic risk for brain-related disorders. Gene coexpression network analysis elucidated interactions among activity-dependent and disease-associated genes and pointed to a key driver (NAV3) that interacted with multiple genes involved in axon guidance. CONCLUSIONS: Overall, we demonstrated that deciphering the activity-dependent regulome in glutamatergic neurons reveals novel targets for advanced diagnosis and therapy.


Assuntos
Células-Tronco Pluripotentes Induzidas , Esquizofrenia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Regulação da Expressão Gênica , Neurônios/metabolismo , Encéfalo
16.
medRxiv ; 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38076956

RESUMO

Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. We previously mapped the genetic regulation of gene expression and mRNA splicing in human microglia, identifying several loci where common genetic variants in microglia-specific regulatory elements explain disease risk loci identified by GWAS. However, identifying genetic effects on splicing has been challenging due to the use of short sequencing reads to identify causal isoforms. Here we present the isoform-centric microglia genomic atlas (isoMiGA) which leverages the power of long-read RNA-seq to identify 35,879 novel microglia isoforms. We show that the novel microglia isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ethnic meta-analysis of 555 human microglia short-read RNA-seq samples from 391 donors, the largest to date, and found associations with genetic risk loci in Alzheimer's disease and Parkinson's disease. We nominate several loci that may act through complex changes in isoform and splice site usage.

17.
medRxiv ; 2023 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-37873320

RESUMO

Non-coding variants increase risk of neuropsychiatric disease. However, our understanding of the cell-type specific role of the non-coding genome in disease is incomplete. We performed population scale (N=1,393) chromatin accessibility profiling of neurons and non-neurons from two neocortical brain regions: the anterior cingulate cortex and dorsolateral prefrontal cortex. Across both regions, we observed notable differences in neuronal chromatin accessibility between schizophrenia cases and controls. A per-sample disease pseudotime was positively associated with genetic liability for schizophrenia. Organizing chromatin into cis- and trans-regulatory domains, identified a prominent neuronal trans-regulatory domain (TRD1) active in immature glutamatergic neurons during fetal development. Polygenic risk score analysis using genetic variants within chromatin accessibility of TRD1 successfully predicted susceptibility to schizophrenia in the Million Veteran Program cohort. Overall, we present the most extensive resource to date of chromatin accessibility in the human cortex, yielding insights into the cell-type specific etiology of schizophrenia.

18.
Genome Med ; 15(1): 88, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37904203

RESUMO

BACKGROUND: Genotypes are strongly associated with disease phenotypes, particularly in brain disorders. However, the molecular and cellular mechanisms behind this association remain elusive. With emerging multimodal data for these mechanisms, machine learning methods can be applied for phenotype prediction at different scales, but due to the black-box nature of machine learning, integrating these modalities and interpreting biological mechanisms can be challenging. Additionally, the partial availability of these multimodal data presents a challenge in developing these predictive models. METHOD: To address these challenges, we developed DeepGAMI, an interpretable neural network model to improve genotype-phenotype prediction from multimodal data. DeepGAMI leverages functional genomic information, such as eQTLs and gene regulation, to guide neural network connections. Additionally, it includes an auxiliary learning layer for cross-modal imputation allowing the imputation of latent features of missing modalities and thus predicting phenotypes from a single modality. Finally, DeepGAMI uses integrated gradient to prioritize multimodal features for various phenotypes. RESULTS: We applied DeepGAMI to several multimodal datasets including genotype and bulk and cell-type gene expression data in brain diseases, and gene expression and electrophysiology data of mouse neuronal cells. Using cross-validation and independent validation, DeepGAMI outperformed existing methods for classifying disease types, and cellular and clinical phenotypes, even using single modalities (e.g., AUC score of 0.79 for Schizophrenia and 0.73 for cognitive impairment in Alzheimer's disease). CONCLUSION: We demonstrated that DeepGAMI improves phenotype prediction and prioritizes phenotypic features and networks in multiple multimodal datasets in complex brains and brain diseases. Also, it prioritized disease-associated variants, genes, and regulatory networks linked to different phenotypes, providing novel insights into the interpretation of gene regulatory mechanisms. DeepGAMI is open-source and available for general use.


Assuntos
Doença de Alzheimer , Aprendizado de Máquina , Animais , Camundongos , Redes Neurais de Computação , Genótipo , Fenótipo , Doença de Alzheimer/genética
19.
Sci Adv ; 9(41): eadg3754, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37824614

RESUMO

The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that is mediated, in part, by the spatiotemporal activity of cis-regulatory elements (CREs). We simultaneously profiled gene expression and chromatin accessibility in 45,549 cortical nuclei across six broad developmental time points from fetus to adult. We identified cell type-specific domains in which chromatin accessibility is highly correlated with gene expression. Differentiation pseudotime trajectory analysis indicates that chromatin accessibility at CREs precedes transcription and that dynamic changes in chromatin structure play a critical role in neuronal lineage commitment. In addition, we mapped cell type-specific and temporally specific genetic loci implicated in neuropsychiatric traits, including schizophrenia and bipolar disorder. Together, our results describe the complex regulation of cell composition at critical stages in lineage determination and shed light on the impact of spatiotemporal alterations in gene expression on neuropsychiatric disease.


Assuntos
Cromatina , Multiômica , Humanos , Cromatina/genética , Cromatina/metabolismo , Sequências Reguladoras de Ácido Nucleico , Diferenciação Celular/genética , Encéfalo/metabolismo
20.
Res Sq ; 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37886514

RESUMO

Non-coding variants increase risk of neuropsychiatric disease. However, our understanding of the cell-type specific role of the non-coding genome in disease is incomplete. We performed population scale (N=1,393) chromatin accessibility profiling of neurons and non-neurons from two neocortical brain regions: the anterior cingulate cortex and dorsolateral prefrontal cortex. Across both regions, we observed notable differences in neuronal chromatin accessibility between schizophrenia cases and controls. A per-sample disease pseudotime was positively associated with genetic liability for schizophrenia. Organizing chromatin into cis- and trans-regulatory domains, identified a prominent neuronal trans-regulatory domain (TRD1) active in immature glutamatergic neurons during fetal development. Polygenic risk score analysis using genetic variants within chromatin accessibility of TRD1 successfully predicted susceptibility to schizophrenia in the Million Veteran Program cohort. Overall, we present the most extensive resource to date of chromatin accessibility in the human cortex, yielding insights into the cell-type specific etiology of schizophrenia.

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