Cell Systems, Journal Year: 2025, Volume and Issue: unknown, P. 101204 - 101204
Published: March 1, 2025
Language: Английский
Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(12), P. 1648 - 1659
Published: Nov. 29, 2021
Language: Английский
Citations
118
Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(9), P. 1505 - 1515
Published: Aug. 10, 2023
Language: Английский
Citations
47
Science, Journal Year: 2024, Volume and Issue: 384(6698)
Published: May 23, 2024
Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into resource comprising >2.8 million nuclei from prefrontal cortex across 388 individuals. For 28 cell types, assessed population-level variation in expression and chromatin families drug targets. We identified >550,000 type-specific regulatory elements >1.4 single-cell quantitative trait loci, which used to build cell-type cell-to-cell communication networks. These networks manifest cellular changes aging neuropsychiatric disorders. further constructed an integrative model accurately imputing simulating perturbations; prioritized ~250 disease-risk genes targets with associated types.
Language: Английский
Citations
43
Science, Journal Year: 2024, Volume and Issue: 384(6698)
Published: May 23, 2024
Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility this complex condition are not well understood. We performed deep single-nucleus RNA sequencing (snRNA-seq) examine cell composition transcriptomics, identifying dysregulation of type-specific gene regulatory networks (GRNs) autism spectrum disorder (ASD), which we corroborated using assay for transposase-accessible chromatin with (snATAC-seq) spatial transcriptomics. Transcriptomic were primarily type specific, involving multiple types, most prominently interhemispheric callosal-projecting neurons, interneurons within superficial laminae, distinct glial reactive states oligodendrocytes, microglia, astrocytes. Autism-associated GRN drivers their targets enriched rare common risk variants, connecting cellular circuit alterations the human brain.
Language: Английский
Citations
33
Science, Journal Year: 2024, Volume and Issue: 384(6698)
Published: May 23, 2024
RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, role of cell type-specific transcript-isoform diversity during human development not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing deeply profile full-length transcriptome germinal zone cortical plate regions developing neocortex at tissue single-cell resolution. We identified 214,516 distinct isoforms, which 72.6% were novel (not previously annotated Gencode version 33), uncovered a substantial contribution diversity-regulated by binding proteins-in defining cellular identity neocortex. comprehensive isoform-centric gene annotation reprioritize thousands rare de novo risk variants elucidate genetic mechanisms for disorders.
Language: Английский
Citations
24
Biomedicines, Journal Year: 2024, Volume and Issue: 12(1), P. 210 - 210
Published: Jan. 17, 2024
Microglia, as one of the main types glial cells in central nervous system (CNS), are widely distributed throughout brain and spinal cord. The normal number function microglia very important for maintaining homeostasis CNS. In recent years, scientists have paid widespread attention to role Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder, patients with ASD severe deficits behavior, social skills, communication. Most previous studies on focused neuronal pathological changes, such increased cell proliferation, accelerated differentiation, impaired synaptic development, reduced spontaneous synchronous activity. Currently, more research has found that microglia, immune cells, can promote neurogenesis pruning maintain CNS homeostasis. They usually reduce unnecessary connections early life. Some researchers proposed many phenotypes may be caused by microglial abnormalities. Based this, we summarize ASD, focusing We aim clarify essential factors influenced explore possibility microglia-related pathways potential targets ASD.
Language: Английский
Citations
21
Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(6), P. 1075 - 1086
Published: April 22, 2024
Abstract Human brain organization involves the coordinated expression of thousands genes. For example, first principal component (C1) cortical transcription identifies a hierarchy from sensorimotor to association regions. In this study, optimized processing Allen Brain Atlas revealed two new components gene architecture, C2 and C3, which are distinctively enriched for neuronal, metabolic immune processes, specific cell types cytoarchitectonics, genetic variants associated with intelligence. Using additional datasets (PsychENCODE, Cell BrainSpan), we found that C1–C3 represent generalizable transcriptional programs within cells differentially phased during fetal postnatal development. Autism spectrum disorder schizophrenia were specifically C1/C2 respectively, across neuroimaging, differential genome-wide studies. Evidence converged especially in support C3 as normative program adolescent development, can lead atypical supragranular connectivity people at high risk schizophrenia.
Language: Английский
Citations
20
MedComm, Journal Year: 2024, Volume and Issue: 5(3)
Published: March 1, 2024
Abstract Autism spectrum disorder (ASD) has become a common neurodevelopmental disorder. The heterogeneity of ASD poses great challenges for its research and clinical translation. On the basis reviewing ASD, this review systematically summarized current status progress pathogenesis, diagnostic markers, interventions ASD. We provided an overview molecular mechanisms identified by multi‐omics studies convergent mechanism in different genetic backgrounds. comorbidities, associated with important physiological metabolic abnormalities (i.e., inflammation, immunity, oxidative stress, mitochondrial dysfunction), gut microbial were reviewed. non‐targeted omics targeting markers also Moreover, we methods behavioral educational interventions, intervention related to technological devices, on medical potential drug targets. This highlighted application high‐throughput emphasized importance seeking homogeneity from exploring convergence disease mechanisms, biomarkers, approaches, proposes that taking into account individuality commonality may be key achieve accurate diagnosis treatment
Language: Английский
Citations
18
medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 15, 2025
Abstract Psychiatric disorders display high levels of comorbidity and genetic overlap 1,2 . Genomic methods have shown that even for schizophrenia bipolar disorder, two long-thought to be etiologically distinct 3 , the majority signal is shared 4 Furthermore, recent cross-disorder analyses uncovered over a hundred pleiotropic loci across eight 5 However, full scope disorder-specific basis psychopathology remains largely uncharted. Here, we address this gap by triangulating suite cutting-edge statistical functional genomic applied 14 childhood- adult-onset psychiatric (1,056,201 cases). Our identify characterize five underlying factors 6 explain variance individual (∼66% on average) are associated with 268 loci. We observed particularly polygenic 7 local correlation 8 very few 9 defined by: ( i ) disorder (“SB factor”), ii major depression, PTSD, anxiety (“internalizing factor”). At level, multiple 10–12 which demonstrated SB factor was substantially enriched in genes expressed excitatory neurons, whereas internalizing oligodendrocyte biology. By comparison, all broad biological processes (e.g., transcriptional regulation). These results indicate increasing differentiation function at different risk, from quite general vulnerability more specific pathways subsets disorders. observations may inform neurobiologically valid nosology implicate novel targets therapeutic developments designed treat commonly occurring comorbid presentations.
Language: Английский
Citations
2
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 22, 2025
The diversity of genes implicated in autism spectrum disorder (ASD) creates challenges for identifying core pathophysiological mechanisms. Aggregation seven different classes genetic variants ASD, a database we call Consensus-ASD , reveals shared features across distinct types ASD variants. Functional interrogation 19 and 9 neighboring long non-coding RNAs (lncRNAs) using CRISPR-Cas13 strikingly revealed differential gene expression profiles that were significantly enriched other genes. Furthermore, construction regulatory network (GRN) enabled the identification central regulators exhibit convergently altered activity upon disruption. Thus, this study how perturbing ASD-associated can lead to shared, broad dysregulation GRNs with critical relevance ASD. This provides crucial framework understanding diverse genes, including lncRNAs, play convergent roles key neurodevelopmental processes ultimately contribute
Language: Английский
Citations
2