Large-Scale Mendelian Randomization Study Reveals Circulating Blood-based Proteomic Biomarkers for Psychopathology and Cognitive Task Performance DOI Creative Commons
Upasana Bhattacharyya,

Jibin John,

Max Lam

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 20, 2024

Abstract Background Research on peripheral (e.g., blood-based) biomarkers for psychiatric illness has typically been low-throughput in terms of both the number subjects and range assays performed. Moreover, traditional case-control studies examining blood-based are subject to potential confounds treatment other exposures common patients with illnesses. Our research addresses these challenges by leveraging large-scale, high-throughput proteomics data Mendelian Randomization (MR) examine causal impact circulating proteins phenotypes cognitive task performance. Methods We utilized plasma from UK Biobank (3,072 assayed 34,557 European-ancestry individuals) deCODE Genetics (4,719 measured across 35,559 Icelandic individuals). Significant proteomic quantitative trait loci (both cis-pQTLs trans-pQTLs) served as MR instruments, most recent GWAS schizophrenia, bipolar disorder, major depressive performance (all excluding overlapping participants) phenotypic outcomes. Results revealed 109 Bonferroni-corrected associations (44 novel) involving 88 four phenotypes. Several immune-related proteins, including interleukins complement factors, stood out pleiotropic multiple outcome Drug target enrichment analysis identified several novel pharmacologic repurposing opportunities, anti-inflammatory agents schizophrenia disorder duloxetine Conclusions Identification effects suggests conditions offers insights developing innovative therapeutic strategies. The findings also indicate substantial evidence many different phenotypes, shedding light shared etiology among ability.

Language: Английский

The gut microbiome and mental health: advances in research and emerging priorities DOI
Andrew P. Shoubridge, Jocelyn M. Choo, Alyce M. Martin

et al.

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 27(4), P. 1908 - 1919

Published: March 2, 2022

Language: Английский

Citations

82
Bringing machine learning to research on intellectual and developmental disabilities: taking inspiration from neurological diseases DOI Creative Commons
Chirag Gupta, Pramod Chandrashekar, Ting Jin

et al.

Journal of Neurodevelopmental Disorders, Journal Year: 2022, Volume and Issue: 14(1)

Published: May 2, 2022

Intellectual and Developmental Disabilities (IDDs), such as Down syndrome, Fragile X Rett autism spectrum disorder, usually manifest at birth or early childhood. IDDs are characterized by significant impairment in intellectual adaptive functioning, both genetic environmental factors underpin IDD biology. Molecular stratification of remain challenging mainly due to overlapping comorbidity. Advances high throughput sequencing, imaging, tools record behavioral data scale have greatly enhanced our understanding the molecular, cellular, structural, basis some IDDs. Fueled "big data" revolution, artificial intelligence (AI) machine learning (ML) technologies brought a whole new paradigm shift computational Evidently, ML-driven approach clinical diagnoses has potential augment classical methods that use symptoms external observations, hoping push personalized treatment plan forward. Therefore, integrative analyses applications ML technology direct bearing on discoveries The application can potentially improve screening diagnosis, advance complexity comorbidity, accelerate identification biomarkers for research drug development. For more than five decades, IDDRC network supported nexus investigators centers across USA, all striving understand interplay between various underlying In this review, we introduced fast-increasing multi-modal types, highlighted example studies employed illuminate biological mechanisms IDDs, well recent advances their other neurological diseases. We discussed clinical, collection modes, including genetic, phenotypical, along with multiple repositories store share data. Furthermore, outlined fundamental concepts algorithms presented opinion specific gaps will need be filled accomplish, example, reliable implementation ML-based diagnosis clinics. anticipate review guide researchers formulate AI approaches investigate related conditions.

Language: Английский

Citations

35
Circuits regulating pleasure and happiness – focus on potential biomarkers for circuitry including the habenuloid complex DOI Creative Commons
A.J.M. Loonen, Svetlana А. Ivanova

Acta Neuropsychiatrica, Journal Year: 2022, Volume and Issue: 34(5), P. 229 - 239

Published: May 19, 2022

The multiplicity and complexity of the neuronal connections in central nervous system make it difficult to disentangle circuits that play an essential role development or treatment (neuro)psychiatric disorders. By choosing evolutionary forebrain as a starting point, certain order can be created. dorsal diencephalic connection (DDC) applied for biomarkers predict response.After providing brief introduction theory, we examined neuroanatomical publications on connectivity DDC system. We then searched neurochemical components are specific habenula.The best strategy find reflect function habenular is use genetic variants receptors, transporters enzymes this complex. activating these with probes measuring response people different functional genotypes, usefulness assessed.The most promising respect those linked activation inhibition nicotine receptor, dopamine D4 μ-opioid receptor also functioning glia cells (astrocytes microglia).

Language: Английский

Citations

34
IUPHAR review: Drug Repurposing in Schizophrenia – An Updated Review of Clinical Trials DOI Creative Commons
Jihan K. Zaki, Jakub Tomasik,

Sabine Bahn

et al.

Pharmacological Research, Journal Year: 2025, Volume and Issue: unknown, P. 107633 - 107633

Published: Jan. 1, 2025

There is an urgent need for mechanistically novel and more efficacious treatments schizophrenia, especially those targeting negative cognitive symptoms with a favorable side-effect profile. Drug repurposing-the process of identifying new therapeutic uses already approved compounds-offers promising approach to overcoming the lengthy, costly, high-risk traditional CNS drug discovery. This review aims update our previous findings on clinical repurposing pipeline in schizophrenia. We examined studies conducted between 2018 2024, 61 trials evaluating 40 unique repurposed candidates. These encompassed broad range pharmacological mechanisms, including immunomodulation, enhancement, hormonal, metabolic, neurotransmitter modulation. A notable development combination muscarinic modulators xanomeline, compound antipsychotic properties, trospium, included mitigate peripheral side effects, now by FDA as first decades fundamentally mechanism action. Moving beyond dopaminergic paradigm such highlight opportunities improve treatment-resistant alleviate adverse effects. Overall, evolving landscape illustrates significant shift rationale schizophrenia development, highlighting potential silico strategies, biomarker-based patient stratification, personalized that align underlying pathophysiological processes.

Language: Английский

Citations

1
Protein arginine methyltransferase 7 linked to schizophrenia through regulation of neural progenitor cell proliferation and differentiation DOI Creative Commons
Ting Shen,

Jing Yu,

Bin Xie

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(2), P. 115279 - 115279

Published: Feb. 1, 2025

Genome-wide association studies (GWASs) have identified numerous genomic loci linked to schizophrenia (SCZ), while their pathogenic mechanisms largely remain unclear. This study demonstrated protein arginine methyltransferase 7 (PRMT7) as a key target of SCZ risk SNPs with allele-specific enhancer activity at 16q22.1. Downregulating PRMT7 in neural progenitor cells (NPCs) decreased proliferation, increased neuronal differentiation, and also led longer neurites these neurons. Conversely, overexpressing enhanced NPC proliferation reduced differentiation. In three-dimensional (3D) cerebral organoids, similar phenotypic changes were noted following depletion. Mechanistically, regulates the expression genes related cell cycle functions, such CDKN2A SYP, via symmetrical di-methylation 3 histone 4 (H4R3me2s) modification promoters. Notably, stronger compared other mental disorders. Together, results this reveal that is functional gene 16q22.1, contributing etiology by modulating differentiation an epigenetic regulator.

Language: Английский

Citations

1
Acylcarnitines metabolism in depression: association with diagnostic status, depression severity and symptom profile in the NESDA cohort DOI Creative Commons
Silvia Montanari, Rick Jansen, Daniela Schranner

et al.

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 23, 2025

Language: Английский

Citations

1
Updated perspectives on the clinical significance of negative symptoms in patients with schizophrenia DOI Creative Commons
Giulia Maria Giordano, Edoardo Caporusso, Pasquale Pezzella

et al.

Expert Review of Neurotherapeutics, Journal Year: 2022, Volume and Issue: 22(7), P. 541 - 555

Published: June 27, 2022

Negative symptoms in schizophrenia are associated with poor response to available treatments, quality of life, and functional outcome. Therefore, they represent a substantial burden for people schizophrenia, their families, health-care systems.In this manuscript, we will provide an update on the conceptualization, assessment, treatment complex psychopathological dimension schizophrenia.Despite progress conceptualization negative development state-of-the-art assessment instruments made last decades, these still poorly recognized, not always assessed line current conceptualization. Every effort should be disseminate knowledge symptoms, treatments whose efficacy is supported by research evidence. Longitudinal studies promoted evaluate natural course improve our ability identify different sources secondary effective interventions, target primary persistent innovative strategies. Further needed pathophysiological mechanisms foster new treatments.

Language: Английский

Citations

29
The Homer1 family of proteins at the crossroad of dopamine-glutamate signaling: An emerging molecular “Lego” in the pathophysiology of psychiatric disorders. A systematic review and translational insight DOI
Andrea de Bartolomeis, Annarita Barone, Elisabetta Filomena Buonaguro

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2022, Volume and Issue: 136, P. 104596 - 104596

Published: March 4, 2022

Language: Английский

Citations

24
Schizophrenia and psychedelic state: Dysconnection versus hyper-connection. A perspective on two different models of psychosis stemming from dysfunctional integration processes DOI
Jacopo Sapienza, Marta Bosia, Marco Spangaro

et al.

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(1), P. 59 - 67

Published: Aug. 5, 2022

Language: Английский

Citations

20
Genetic Insights of Schizophrenia via Single Cell RNA-Sequencing Analyses DOI Creative Commons
Yong Wu, Chuyi Zhang, Lu Wang

et al.

Schizophrenia Bulletin, Journal Year: 2023, Volume and Issue: 49(4), P. 914 - 922

Published: Feb. 20, 2023

Abstract Background Schizophrenia is a complex and heterogeneous disorder involving multiple regions types of cells in the brain. Despite rapid progress made by genome-wide association studies (GWAS) schizophrenia, mechanisms illness underlying GWAS significant loci remain less clear. Study Design We investigated schizophrenia risk genes using summary-data-based Mendelian randomization based on single-cell sequencing data, explored brain involved through expression weighted cell-type enrichment analysis. Results identified 54 (two-thirds these were not data bulk tissues) RNA-sequencing data. Further cell type analysis showed that highly expressed excitatory neurons caudal ganglionic eminence interneurons, suggesting putative roles pathogenesis schizophrenia. also found results could form large protein-protein interaction network with affected disease-causing rare variants. Conclusions Through integrative analyses at levels, we associated Notably, many only their altered levels particular cells, rather than tissues, related to increased Our provide novel insight into biological future are necessary further facilitate understanding disorder.

Language: Английский

Citations

12