Coordinated dysregulation of modular gene activity in human neuropathologies
Year: 2026
Type: preprint
Abstract: ABSTRACT Understanding which genes are reproducibly dysregulated in which cell types is foundational knowledge for efforts to slow or reverse pathologies. For neuropathologies, such efforts rely primarily on differential expression analysis of single-nucleus RNA-seq (snRNA-seq) data. However, this strategy suffers from experimental and statistical challenges that limit marker gene reproducibility. We describe a novel strategy called Covariation Projection Analysis ( CoPA ) that combines the power of bulk sampling with the precision of single-cell methods. By ‘projecting’ bulk gene coexpression modules onto pseudobulked snRNA-seq cell types, CoPA reveals the cellular origins of highly reproducible genomic programs and their relative importance among cell types. By comparing CoPA projection patterns between normal and pathological human brain samples using d ifferential CoPA ( dCoPA ), we identify gene coexpression modules that are uniformly and reproducibly dysregulated in specific neocortical cell types in Alzheimer’s disease or schizophrenia. We share our findings through a novel web application called CoPA Cabana ( https://oldhamlab.shinyapps.io/copacabana/ ).
Authors: Gugene Kang, Michael C. Oldham
Institution: University of California, San Francisco
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Inhibition, Oscillations and Information Processing in Schizophrenia, Epidemiologic Study of Neural Reserve and Neurobiology of Aging, Integrative Genomics of the Corticolimbic Circuit in Major Depressive Disorder, Developmental Trajectories of Negative Symptoms in Schizophrenia, 2/3 High-resolution mapping of cell type-specific DNA (hydroxy)methylation in the human brain during postnatal development and in psychiatric disease, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, 3/3 High-resolution mapping of cell type-specific DNA (hydroxy)methylation in the human brain during postnatal development and in psychiatric disease, Identifying therapeutic targets for autism using Shank3-deficient mice, Graduate Training in Computational and Systems Biology, 1/3 Integrative Genomic Analysis of Human Brain Development and Autism, Epigenomic, transcriptional and cellular dissection of Alzheimer's variants, 1/2 Discovery and validation of neuronal enhancers associated with the development of psychiatric disorders, Spatial registration of gene expression in the human brain, Single-cell transcriptional and epigenomic dissection of Alzheimer's Disease and Related Dementias, Transcriptional and Epigenetic Signatures of Human Brain Development and Autism, Elucidating the Molecular Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Disease, Single Cell Transcriptional and Epigenomic Dissection of Schizophrenia and Bipoloar Disease, Interpreting non-coding variants using epigenomics, regulatory models, & validation experiments, White Matter Abnormalities in Schizophrenia, Exploring the Role of the Brain Transcriptome in Cognitive Decline, Construction of an Integrated Immune - Vascular Brain - Chip as a Platform for the Study, Drug Screening, and Treatments of Alzheimer's Disease, 2/2 Discovery and validation of neuronal enhancers associated with the development of psychiatric disorders, Alzheimer's Disease Patient Registry (ADPR/ACT), Cell type specific epigenetic analysis to understand complex mechanisms underlying Alzheimer's disease phenotypes, Long non-coding RNAs in gene regulatory networks underlying Autism, Decomposing cell type-specific marks in post-mortem human brain studies, 1/2 Measuring translational dynamics and the proteome to identify potential brain biomakers for psychiatric disease, Alzheimer's Disease Research Center, Gene regulatory elements and transcriptome in iPSCs and embryonic human cortex, 2/3 Integrative Genomic Analysis of Human Brain Development and Autism, Pathway discovery, validation and compound identification for Alzheimer's disease, Risk genetic variants and cis regulation of gene expression in Bipolar Disorder, 3/3 Chromatin regulation during brain development and in ASD, Src hypoactivity as a mediator of various molecular alterations leading to NMDAR, Decoding the molecular basis of cellular identity in adult malignant gliomas, 2/3 Chromatin regulation during brain development and in ASD, International Cohort Collection for Bipolar Disorder, Genetics Association in Schizophrenia and Other Disorders, Risk Factors, Pathology, and Clinical Expressions of AD, Rush Alzheimer's Disease Core Center, Dissection of endosomal trafficking mechanisms in Alzheimer's Disease, Integrated Multiscale Networks in Schizophrenia, Multiscale transcriptional architecture of the human brain, Genetic variants affect brain gene expression and risks of psychiatric disorders, Establishing comprehensive and quantitative maps of DNA methylation in the develo, Decoding schizophrenia-From GWAS to functional regulatory variants, Demystifying Microglia in Aging and Alzheimer's Disease, 1/3-Networks from Multidimensional Data for Schizophrenia and Related Disorders, Multi-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targets, 1/3 Chromatin regulation during brain development and in ASD, Dynamic RNA Modifications in human brain development and autism, Functional Genomics of Human Brain Development, 2/2-Measuring translational dynamics and the proteome to identify potential brain biomarkers for psychiatric disease, Cis-Regulatory Epigenome Mappings in Schizophrenia, RNA Sequencing of the Limbic System in Bipolar Disorder, Plasma and CSF Abeta peptides in late-onset major depression, Construction of an integrated immune - vascular brain - chip as a platform for the study, drug screening, and treatments of Alzheimer's disease, The 3D genome in transcriptional regulation across the postnatal life span, with implications for schizophrenia and bipolar disorder, Functional genomic resource and integrative model of dopaminergic circuitry associated with psychiatric disease, GABA Epigenomes in Autism, Epigenetic and Transcriptional Dysregulation in Autism Spectrum Disorder, Mapping the role of long noncoding RNAs in gene regulatory networks in schizophrenia, Alzheimer's Disease Research Center, Characterizing the developing human brain transcriptome at single-base resolution, The USC PsychENCODE Project, 3/3 Integrative Genomic Analysis of Human Brain Development and Autism, Massively parallel characterization of psychiatric disease associated regulatory elements in defined cell types, 1/3 High-resolution mapping of cell type-specific DNA (hydroxy)methylation in the human brain during postnatal development and in psychiatric disease., Clinical and Biological Studies of Early AD, Molecular Profiling of Schizophrenia, Decoding the molecular basis of cellular identity in the human brain, 1/2 Cell Type and Region-Specific Regulatory Networks in Human Brain Development and Disorders, Genome wide SNP analysis in Parkinson's disease, Adult Changes in Thought (ACT) Research Program, Identification of TDP-43 Modifiers Through Single-Cell Transcriptional and Epigenomic Dissection of ALS and FTLD-MND, 1/3 Understanding PTSD through Postmortem Targeted Brain Multi-omics, Site 3/3, Understanding PTSD through Postmortem Targeted Brain Multiomics, Identifying and exploiting molecular abnormalities of tumor vasculature, University of Washington Alzheimer's Disease Research Center, Single-cell epigenomic and trancriptional dissection of sex-specific differences in Alzheimer’s Disease, 2/3 Understanding PTSD through Postmortem Targeted Brain Multi-omics, Rush Alzheimer's Disease Research Center, A multimodal brain cell atlas and community resource of Alzheimer's disease and comorbid dementias.
OpenAlex ID: W7204651564