Identifying drug targets for schizophrenia through gene prioritization DOI Creative Commons
Julia Kraft, Alice Braun, Swapnil Awasthi

и другие.

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

Опубликована: Май 16, 2024

Abstract Background Schizophrenia genome-wide association studies (GWASes) have identified >250 significant loci and prioritized >100 disease-related genes. However, gene prioritization efforts mostly been restricted to locus-based methods that ignore information from the rest of genome. Methods To more accurately characterize genes involved in schizophrenia etiology, we applied a combination highly-predictive tools published GWAS 67,390 cases 94,015 controls. We combined both (fine-mapped coding variants, distance signals) (PoPS, MAGMA, ultra-rare variant burden tests). validate our findings, compared them with previous efforts, known neurodevelopmental genes, results PsyOPS tool. Results 62 41 which were also highlighted by validation methods. In addition DRD2 , principal target antipsychotics, 9 are targeted approved or investigational drugs. These included drugs targeting glutamatergic receptors ( GRIN2A GRM3 ), calcium channels CACNA1C CACNB2 GABA B receptor GABBR2 ). shared an addiction e.g. PDE4B VRK2 Conclusions curated high-quality list likely play role development schizophrenia. Developing repurposing these may lead new generation therapies. Rodent models closely resemble human disorder than rodent As such, for disorders could be explored models, potentially facilitating drug development.

Язык: Английский

Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications DOI Creative Commons
Daniel F. Levey, Marco Galimberti, Joseph D. Deak

и другие.

Nature Genetics, Год журнала: 2023, Номер 55(12), С. 2094 - 2103

Опубликована: Ноя. 20, 2023

Abstract As recreational use of cannabis is being decriminalized in many places and medical widely sanctioned, there are growing concerns about increases disorder (CanUD), which associated with numerous comorbidities. Here we performed a genome-wide association study CanUD the Million Veteran Program (MVP), followed by meta-analysis 1,054,365 individuals ( n cases = 64,314) from four broad ancestries designated reference panel used for assignment (European 886,025, African 123,208, admixed American 38,289 East Asian 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant was observed all but smallest population (East Asian). We discovered loci unique ancestry: 22 European, 2 Asian, 1 ancestries. A genetically informed causal relationship analysis indicated possible effect genetic liability on lung cancer risk, suggesting potential unanticipated future psychiatric public health consequences that require further disentangle other known risk factors such as cigarette smoking.

Язык: Английский

Процитировано

52
Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain DOI
Cindy Wen, Michael Margolis, Rujia Dai

и другие.

Science, Год журнала: 2024, Номер 384(6698)

Опубликована: Май 23, 2024

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment regulatory elements in the developing brain. However, prioritizing risk genes mechanisms is challenging without a unified atlas. Across 672 diverse human brains, we identified 15,752 harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing heterogeneity intrinsic properties of neuronal maturation. Isoform-level regulation, particularly second trimester, mediated largest proportion GWAS heritability. Through colocalization, prioritized about 60% loci across five disorders, exceeding adult brain findings. Finally, contextualized results within gene isoform coexpression networks, revealing comprehensive landscape transcriptome regulation development disease.

Язык: Английский

Процитировано

18
Genomics yields biological and phenotypic insights into bipolar disorder DOI
Kevin S. O’Connell, Maria Koromina, Tracey van der Veen

и другие.

Nature, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Язык: Английский

Процитировано

9
Alternative splicing in prostate cancer progression and therapeutic resistance DOI Creative Commons
Chitra Rawat, Hannelore V. Heemers

Oncogene, Год журнала: 2024, Номер 43(22), С. 1655 - 1668

Опубликована: Апрель 24, 2024

Abstract Prostate cancer (CaP) remains the second leading cause of deaths in western men. CaP mortality results from diverse molecular mechanisms that mediate resistance to standard care treatments for metastatic disease. Recently, alternative splicing has been recognized as a hallmark aggressiveness. Alternative events treatment and aggressive behavior are determinants emergence two major types late-stage treatment-resistant CaP, namely castration-resistant (CRPC) neuroendocrine (NEPC). Here, we review recent multi-omics data uncovering complicated landscape during progression impact different gene transcript isoforms can have on cell biology behavior. We discuss renewed insights machinery by which occurs contributes failure systemic therapies. The potential serve diagnostic markers and/or therapeutic targets is explored. conclude considering current challenges promises associated with splicing-modulating therapies, their clinical translation into patient care.

Язык: Английский

Процитировано

8
Quantitative trait loci mapping of circulating metabolites in cerebrospinal fluid to uncover biological mechanisms involved in brain-related phenotypes DOI
Lianne M. Reus, Toni Boltz, Marcelo Francia

и другие.

Molecular Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 28, 2025

Язык: Английский

Процитировано

1
Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms DOI Creative Commons
L. Lambourne, Kaia Mattioli, Clarissa Stephanie Santoso

и другие.

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

Опубликована: Март 14, 2024

Most human Transcription factors (TFs) genes encode multiple protein isoforms differing in DNA binding domains, effector or other regions. The global extent to which this results functional differences between remains unknown. Here, we systematically compared 693 of 246 TF genes, assessing binding, transcriptional activation, subcellular localization, and condensate formation. Relative reference isoforms, two-thirds alternative exhibit one more molecular activities, often could not be predicted from sequence. We observed two primary categories isoforms: "rewirers" "negative regulators", both were associated with differentiation cancer. Our support a model wherein the relative expression levels of, interactions involving, add an understudied layer complexity gene regulatory networks, demonstrating importance isoform-aware characterization functions providing rich resource for further studies.

Язык: Английский

Процитировано

7
Neuron type-specific proteomics reveals distinct Shank3 proteoforms in iSPNs and dSPNs lead to striatal synaptopathy in Shank3B–/– mice DOI Creative Commons
Yizhi Wang,

Tamara Perez‐Rosello,

Samuel N. Smukowski

и другие.

Molecular Psychiatry, Год журнала: 2024, Номер 29(8), С. 2372 - 2388

Опубликована: Март 14, 2024

Abstract Combinatorial expression of postsynaptic proteins underlies synapse diversity within and between neuron types. Thus, characterization neuron-type-specific proteomes is key to obtaining a deeper understanding discrete synaptic properties how selective dysfunction manifests in synaptopathies. To overcome the limitations associated with bulk measures protein abundance, we developed biotin proximity tagging probe characterize vivo. We found Shank3 isoforms are differentially expressed by direct indirect pathway spiny projection neurons (dSPNs iSPNs). Investigation Shank3B –/– mice lacking exons 13–16 gene, reveal distinct isoform iSPNs dSPNs. In -/- striatum, Shank3E Shank3NT dSPNs but undetectable iSPNs. Proteomic analysis indicates significant alterations proteome Correspondingly, deletion diminishes dendritic spine density, reduces head diameter, hampers corticostriatal transmission Remarkably, reintroducing adult significantly rectifies observed morphological deficits. report unexpected cell-type specific which could play causal role specifying

Язык: Английский

Процитировано

5
Cross-ancestry, cell-type-informed atlas of gene, isoform, and splicing regulation in the developing human brain DOI Creative Commons
Cindy Wen, Michael Margolis, Rujia Dai

и другие.

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

Опубликована: Март 6, 2023

Genomic regulatory elements active in the developing human brain are notably enriched genetic risk for neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and bipolar disorder. However, prioritizing specific genes candidate molecular mechanisms underlying these enrichments has been hindered by lack of a single unified large-scale gene atlas development. Here, we uniformly process systematically characterize gene, isoform, splicing quantitative trait loci (xQTLs) 672 fetal samples from unique subjects across multiple ancestral populations. We identify 15,752 harboring significant xQTL map 3,739 eQTLs to cellular context. observe striking drop expression heritability as develops. Isoform-level regulation, particularly second trimester, mediates greatest proportion psychiatric GWAS, compared with eQTLs. Via colocalization TWAS, prioritize biological ~60% GWAS five nearly two-fold that observed adult brain. Finally, build comprehensive set developmentally regulated isoform co-expression networks capturing disorders. Together, this work provides view regulation development well stage-and cell type-informed mechanistic underpinnings

Язык: Английский

Процитировано

11
Dissecting Schizophrenia Biology Using Pleiotropy with Cognitive Genomics DOI Creative Commons
Upasana Bhattacharyya,

Jibin John,

Todd Lencz

и другие.

Biological Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

0
Nucleus Accumbens Proteome Disbalance in an Adolescent Mouse Model of Schizophrenia and Nicotine Misuse Comorbidity DOI Creative Commons
Thainá P. Souza, Andrés Rodríguez-Vega, Ana Carolina Dutra-Tavares

и другие.

Biomedicines, Год журнала: 2025, Номер 13(4), С. 901 - 901

Опубликована: Апрель 8, 2025

Background/Objectives: Schizophrenia and nicotine misuse are a comorbid condition that frequently develops during adolescence. Considering the role of nucleus accumbens (NAcc) as common neurobiological substrate for these psychiatric disorders, label-free proteomics was employed to identify NAcc deregulated proteins in male female mouse models schizophrenia with history adolescent exposure. Methods: Phencyclidine used model schizophrenia, minipump infusions were misuse. Results: Enrichment Reactome pathway protein–protein interaction analyses showed cytoskeleton associated synaptic plasticity mechanisms, energy metabolism, nervous system development affected both sexes. In particular, Ncam1 (Neural cell adhesion molecule 1) could be interest candidate marker disbalance. Its deregulation sexes suggests it lies at core comorbidity pathophysiology. When considering sex-selective effects, Cs (Citrate synthase) Mapk3 (Mitogen-activated protein kinase 3) identified exclusively mice, respectively. Since previously shown medial prefrontal cortex co-modeled mesocortical mesolimbic effect can inferred, supporting aberrant metabolism model. Conclusions: The current data provide insights into proteome disbalance an preclinical combined misuse, pointing relevant pathways early markers comorbidity.

Язык: Английский

Процитировано

0