Genetic implication of prenatal GABAergic and cholinergic neuron development in susceptibility to schizophrenia DOI Creative Commons
Darren Cameron,

Ngoc‐Nga Vinh,

Parinda Prapaiwongs

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 14, 2023

Abstract Background The ganglionic eminences are fetal-specific structures that give rise to gamma- aminobutyric acid (GABA)- and acetylcholine- releasing neurons of the forebrain. Given evidence for GABAergic cholinergic disturbances in schizophrenia, as well an early neurodevelopmental component disorder, we tested potential involvement developing cells mediating genetic risk condition. Study Design We combined data from a recent large-scale genome-wide association study schizophrenia with single cell RNA sequencing human test enrichment variation genes high expression specificity particular populations within these structures. additionally performed nuclei Assay Transposase-Accessible Chromatin Sequencing (snATAC-Seq) map regulatory genomic regions operating individual eminences, using common variant liability functionally annotate non-coding variants associated disorder. Results Schizophrenia was enriched neuron predicted form dopamine D1 D2 receptor expressing medium spiny striatum, cortical somatostatin-positive interneurons, calretinin-positive neurons. Consistent findings, also concentrated sequence mapped neuronal eminences. Conclusions Our provides role prenatal development later susceptibility schizophrenia.

Язык: Английский

Psychiatric Genomics 2025 DOI
Chunyu Liu, Chunling Zhang, Stephen J. Glatt

и другие.

Psychiatric Clinics of North America, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

0
New directions in psychiatric drug development: promising therapeutics in the pipeline DOI
Linda S. Brady, Sarah H. Lisanby, Joshua A. Gordon

и другие.

Expert Opinion on Drug Discovery, Год журнала: 2023, Номер 18(8), С. 835 - 850

Опубликована: Июнь 23, 2023

Psychiatric disorders are a leading cause of disability worldwide, calling for an urgent need new treatments, early detection, intervention, and precision medicine. Drug discovery development in psychiatry continues to expand exciting areas, with several medications approved psychiatric indications by the U.S. Food Administration (FDA) last 5 years.In this review, authors summarize recent drug approvals molecular mechanisms Phase 1-3 clinical disorders. Advances human genetics-driven target identification, emergent technologies such as artificial intelligence-enabled discovery, digital health technologies, biomarker tools strategies testing novel highlighted.There be research focused on understanding natural history, developmental trajectory, pathophysiology identify circuit-based targets. Looking future, vision is emerging, taking advantage advances genetics, technology, multimodal biomarkers accelerate next-generation therapies individuals living mental illnesses.

Язык: Английский

Процитировано

6
Oxygen-induced stress reveals context-specific gene regulatory effects in human brain organoids DOI Creative Commons
Benjamin D. Umans, Yoav Gilad

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 3, 2024

The interaction between genetic variants and environmental stressors is key to understanding the mechanisms underlying neurological diseases. In this study, we used human brain organoids explore how varying oxygen levels expose context-dependent gene regulatory effects. By subjecting a genetically diverse panel of 21 hypoxic hyperoxic conditions, identified thousands changes that are undetectable under baseline with 1,745 trait-associated genes showing effects only in response stress. To capture more nuanced transcriptional patterns, employed topic modeling, which revealed context-specific regulation linked dynamic cellular processes responses, offering deeper modulated brain. These findings underscore importance genotype-environment interactions studies disorders provide new insights into hidden influenced by factors

Язык: Английский

Процитировано

1
Endophenotype 2.0: updated definitions and criteria for endophenotypes of psychiatric disorders, incorporating new technologies and findings DOI Creative Commons
Chunyu Liu, Elliot S. Gershon

Translational Psychiatry, Год журнала: 2024, Номер 14(1)

Опубликована: Дек. 24, 2024

Язык: Английский

Процитировано

1
Trans-Ancestry Analysis of Psychosis Biotypes: Shared Polygenic Risk and Unique Genomic Associations DOI Creative Commons
Elliot S. Gershon, Cuihua Xia, Ney Alliey‐Rodriguez

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Фев. 29, 2024

Abstract The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has categorized psychosis disorders (Schizophrenia, Schizoaffective Disorder and Bipolar Disorder) into three distinct Biotypes, based on neurobiological measurements in a multi-ancestry sample. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Trans-Ancestry PRSs (TAPRSs), which allow PRS analysis samples. Applied to schizophrenia PRS, we found the Khera TAPRS method show superior portability comparable prediction accuracy as compared with Ge method. Biotypes had similar TAPRSs across ancestries. In genomic nine genes isoforms showed significant associations Transcriptome-Wide Association Study (TWAS) gene expression adult brain fetal brain, isoforms. TWAS inflation was successfully controlled by inclusion genotype Principal Components association analyses. Biotype-related diagnosis distributions differ between African American European

Язык: Английский

Процитировано

0
Validation of Enhancer Regions in Primary Human Neural Progenitor Cells using Capture STARR-seq DOI Creative Commons
Sophia C. Gaynor-Gillett, Lijun Cheng,

Manman Shi

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 18, 2024

Abstract Genome-wide association studies (GWAS) and expression analyses implicate noncoding regulatory regions as harboring risk factors for psychiatric disease, but functional characterization of these remains limited. We performed capture STARR-sequencing over 78,000 candidate to identify active enhancers in primary human neural progenitor cells (phNPCs). selected by integrating data from NPCs, prefrontal cortex, developmental timepoints, GWAS. Over 8,000 demonstrated enhancer activity the phNPCs, we linked 2,200 predicted target genes. These genes are involved neuronal disease-associated pathways, including dopaminergic synapse, axon guidance, schizophrenia. functionally validated a subset using mutation CRISPR deletions, demonstrating effects genetic variation on deletion gene expression. Overall, identified thousands highly enhancers, improving our understanding networks underlying brain function disease.

Язык: Английский

Процитировано

0
CellWalker2: multi-omic discovery of hierarchical cell type relationships and their associations with genomic annotations DOI Creative Commons

Zhirui Hu,

Pawel F. Przytycki, Katherine S. Pollard

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 17, 2024

CellWalker2 is a graph diffusion-based method for single-cell genomics data integration. It extends the CellWalker model by incorporating hierarchical relationships between cell types, providing estimates of statistical significance, and adding structures analyzing multi-omics so that gene expression open chromatin can be jointly modeled. Our open-source software enables users to annotate cells using existing ontologies probabilistically match types two or more contexts, including across species. also map genomic regions ontologies, enabling precise annotation elements derived from bulk data, such as enhancers, genetic variants, sequence motifs. Through simulation studies, we show performs better than methods in type mapping. We then use brain immune system demonstrate CellWalker2's ability discover type-specific regulatory programs both conserved divergent complex tissues.

Язык: Английский

Процитировано

0
Single-nucleus transcriptome-wide association study of human brain disorders DOI Creative Commons
Sanan Venkatesh,

Zhenyi Wu,

Marios Anyfantakis

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 5, 2024

Abstract Neuropsychiatric and neurodegenerative disorders exhibit cell-type-specific characteristics 1–8 , yet most transcriptome-wide association studies have been constrained by the use of homogenate brain tissue 9–11 limiting their resolution power. Here, we present a single-nucleus study ( snTWAS ) leveraging RNA sequencing over 6 million nuclei from dorsolateral prefrontal cortex 1,494 donors across three ancestries—European, African, Admixed American. We constructed ancestry-specific single-nucleus-derived transcriptomic imputation models snTIMs including up to 27 non-overlapping cellular populations, enhancing genetically regulated gene expression GReX in uncovering novel gene-trait associations 12 neuropsychiatric traits. Our framework revealed dysregulation GReX, identifying 4,000 not detected bulk approaches. By applying these Million Veteran Program, validated major findings explored pleiotropy revealing cross-ancestry concordance fine-mapping causal genes. This approach enhances discovery biologically relevant pathways targets, highlighting importance cell-type understanding genetic architecture complex disorders.

Язык: Английский

Процитировано

0
Hierarchical annotation of eQTLs enables identification of genes with cell-type divergent regulation DOI Creative Commons
Pawel F. Przytycki, Katherine S. Pollard

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 16, 2023

Abstract While context-type-specific regulation of genes is largely determined by cis-regulatory regions, attempts to identify cell-type specific eQTLs are complicated the nested nature cell types. We present a network-based model for hierarchical annotation bulk-derived levels type tree using single chromatin accessibility data and no clustering cells into discrete Using our model, we annotated from developing brain with high specificity hierarchy. The increased power provided allowed sensitive detection multiple distinct non-coding elements regulating their expression in different types, which validated single-cell multiome reporter assays. Overall, find that incorporating organization types provides powerful way account relationships between complex tissues.

Язык: Английский

Процитировано

1
Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis DOI Creative Commons

Nil Aygün,

Oleh Krupa,

Jessica Mory

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Сен. 1, 2023

Summary The function of some genetic variants associated with brain-relevant traits has been explained through colocalization expression quantitative trait loci (eQTL) conducted in bulk post-mortem adult brain tissue. However, many brain-trait have unknown cellular or molecular function. These may exert context-specific on different phenotypes including post-transcriptional changes. Here, we identified regulation RNA-editing and alternative polyadenylation (APA), within a cell-type-specific population human neural progenitors neurons. More isoforms utilizing longer sequences were observed neurons, likely due to higher genes encoding the proteins mediating these events. We also detected hundreds editing (edQTLs) QTLs (apaQTLs). found colocalizations neuron edQTL CCDC88A educational attainment progenitor apaQTL EP300 schizophrenia, suggesting genetically mediated during development lead differences

Язык: Английский

Процитировано

0