Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Cell, Год журнала: 2020, Номер 180(3), С. 568 - 584.e23

Опубликована: Янв. 23, 2020

Язык: Английский

---

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Cell, Год журнала: 2019, Номер 179(7), С. 1469 - 1482.e11

Опубликована: Дек. 1, 2019

Язык: Английский

---

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

Science, Год журнала: 2018, Номер 362(6420)

Опубликована: Дек. 13, 2018

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments transcriptomic organization diseased brains are limited. In this work, we integrated genotypes RNA sequencing brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, bipolar disorder, as well controls. More than 25% the transcriptome exhibits differential splicing or expression, isoform-level changes capturing largest effects enrichments. Coexpression networks isolate disease-specific neuronal alterations, microglial, astrocyte, interferon-response modules defining previously unidentified neural-immune mechanisms. We genomic data to perform a transcriptome-wide association study, prioritizing loci likely mediated by cis on expression. This characterization molecular pathology across three major disorders provides resource mechanistic insight therapeutic development.

Язык: Английский

---

Comprehensive functional genomic resource and integrative model for the human brain

Science, Год журнала: 2018, Номер 362(6420)

Опубликована: Дек. 13, 2018

Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource adult brain across 1866 individuals. The contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles many cell types; quantitative-trait loci (QTLs); further QTLs associated with chromatin, splicing, cell-type proportions. Integration shows that varying proportions largely account cross-population variation (with >88% reconstruction accuracy). It also allows building gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic scores identifies key pathways disorders.

Язык: Английский

---

The Human and Mouse Enteric Nervous System at Single-Cell Resolution

Cell, Год журнала: 2020, Номер 182(6), С. 1606 - 1622.e23

Опубликована: Сен. 1, 2020

Язык: Английский

---

Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders

Cell, Год журнала: 2019, Номер 177(1), С. 162 - 183

Опубликована: Март 1, 2019

Язык: Английский

---

Critical period regulation across multiple timescales

Proceedings of the National Academy of Sciences, Год журнала: 2020, Номер 117(38), С. 23242 - 23251

Опубликована: Июнь 5, 2020

Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in physiological range milliseconds (real time), these trajectories are also influenced on longer timescales developmental time (nurture) and evolutionary (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress biological basis a unifying rubric for understanding multiple timescales. Notably, maturation parvalbumin-positive (PV) inhibitory neurons pivotal. These fast-spiking cells generate gamma oscillations associated with period plasticity, sensitive to circadian gene manipulation, emerge at different rates brain regions, acquire perineuronal nets age, may be by epigenetic factors over generations. features provide further novel insight into impact adversity neurodevelopmental risk mental disorders.

Язык: Английский

---

Spatiotemporal transcriptomic divergence across human and macaque brain development

Science, Год журнала: 2018, Номер 362(6420)

Опубликована: Дек. 13, 2018

INTRODUCTION Improved understanding of how the developing human nervous system differs from that closely related nonhuman primates is fundamental for teasing out human-specific aspects behavior, cognition, and disorders. RATIONALE The shared unique functional properties are rooted in complex transcriptional programs governing development distinct cell types, neural circuits, regions. However, precise molecular mechanisms underlying features have been only minimally characterized. RESULTS We generated complementary tissue-level single-cell transcriptomic datasets up to 16 brain regions covering prenatal postnatal humans rhesus macaques ( Macaca mulatta ), a species most commonly studied primate. created applied TranscriptomeAge TempShift algorithms age-match specimens between more rigorously identify temporal differences gene expression within across species. By analyzing regional patterns both macaque brain, comparing these dataset included information adult chimpanzee, we identified divergent development. Furthermore, integration with single-nucleus data periods revealed developmental divergence can be traced types enriched different times regions, including prefrontal cortex, region associated distinctly cognition behavior. found two phases prominent differences: embryonic late midfetal adolescence/young adulthood. This evolutionary cup-shaped or hourglass-like pattern, high adulthood lower early development, resembles pattern described accompanying study by Li et al . Even though (ontogenetic) (phylogenetic) similar profiles, overlap genes driving not substantial, indicating existence constraints specification divergence. Notably, also numerous coexpression modules exhibiting human-distinct either (heterochronic) spatial (heterotopic) expression, as well linked autism spectrum disorder, schizophrenia, other neurological psychiatric diseases. finding potentially suggests mechanistic underpinnings CONCLUSION Our provides insights into evolution may shed some light on certain neuropsychiatric Concerted ontogenetic phylogenetic brain. Left: Human spanning were age-matched using TranscriptomeAge. Right: Phylogenetic each species, during period (from perinatal adolescence). Single-cell transcriptomics types.

Язык: Английский

---

Development and Arealization of the Cerebral Cortex

Neuron, Год журнала: 2019, Номер 103(6), С. 980 - 1004

Опубликована: Сен. 1, 2019

Язык: Английский

---

Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution

Cell, Год журнала: 2021, Номер 184(19), С. 5053 - 5069.e23

Опубликована: Авг. 13, 2021

Язык: Английский

---