Why hasn’t genetics taught us more about schizophrenia?

The Transmitter, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Gene dosage architecture across complex traits

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 26, 2025

Copy number variants (CNVs) have large effects on complex traits, but they are rare and remain challenging to study. As a result, our understanding of biological functions linking gene dosage traits remains limited, whether these sensitive similar those underlying the single nucleotide (SNVs) common unknown. We developed FunBurd, functional burden analysis, test association CNVs aggregated within sets. applied this approach in 500,000 individuals from UK Biobank associate 43 with disrupting 172 sets across tissues cell types. compared CNV findings LoF (Loss Function) SNVs same cohort using All showed FDR significant associations CNVs. Brain tissue neuronal cell-types highest levels pleiotropy. Most set could, part, be explained by genetic constraint, except for brain related processes. Shared contributions between pairs were concordant types variants, average 2-fold higher, variants.Functional enrichment found limited overlap variants. Moreover, deletions duplications negatively correlated most traits.In conclusion, we present new methods separate constraint function traits. Overall, convergence different -even duplications- limited. limited.FunBurd (functional analysis) was UKBiobank tissues/cell type sets.All brain-related higher The Our provide insights

Язык: Английский

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Does Cannabis Use Contribute to Schizophrenia? A Causation Analysis Based on Epidemiological Evidence

Biomolecules, Год журнала: 2025, Номер 15(3), С. 368 - 368

Опубликована: Март 4, 2025

Cannabis abuse has been linked to acute psychotic symptoms as well the development of schizophrenia. Although association described, causation not yet investigated. Therefore, we investigated whether cannabis or cannabinoid use is causal for schizophrenia, conducting a systematic literature review according PRISM guidelines. Epidemiological studies and randomized clinical trials investigating links between psychosis-like events (PLE) schizophrenia were identified (according guidelines), relevant included in Forest plot analysis. Confounder analysis was performed using funnel plot, Hill causality criteria used estimate causation. A total 18 fulfilled search criteria; 10 forest plot. All reported an increased risk PLE nine ten studies, significant increase; overall OR calculated be 2.88 (CI 2.24 3.70), with twofold-higher during adolescence. effects indicated by The high likelihood contribution development. Cannabinoids likely contribute chronic especially if taken This effect increases THC concentration frequency use, stronger males than females. points possibility selective toxicity on synaptic plasticity adolescence, compared adult use. should regulated discouraged, prevention efforts strengthened, reference

Язык: Английский

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IUPHAR Review - Novel therapeutic targets for schizophrenia treatment: a translational perspective

Pharmacological Research, Год журнала: 2025, Номер unknown, С. 107690 - 107690

Опубликована: Март 1, 2025

Schizophrenia is a severe and debilitating psychiatric disorder that profoundly impacts cognitive, emotional, social functioning. Despite its devastating personal societal toll, current treatments often provide only partial relief, underscoring the urgent need for innovative therapeutic strategies. This review explores emerging approaches target complex neurobiological underpinnings of schizophrenia, moving beyond traditional dopamine-centric models. Among these, some novel drugs still employ multimodal mechanisms, simultaneously targeting dopaminergic serotonergic systems to enhance efficacy tolerability. Given well-documented excitatory/inhibitory imbalance in significant efforts have been directed toward addressing NMDA receptor hypofunctionality. However, strategies this pathway yet demonstrate consistent clinical efficacy. In contrast, therapies cholinergic system shown greater promise. For instance, xanomeline-trospium combination, which modulates muscarinic receptors, has recently gained approval, other molecules with similar mechanisms are currently under development. Beyond these approaches, being explored pathways, including neuroplasticity, neuroinflammation, mitochondrial dysfunction. These designed as part combinatorial strategy available antipsychotic drugs. progress, challenges remain translating experimental discoveries into effective applications. Future research should prioritize biomarker-driven precision medicine optimize individualized treatment outcomes. By integrating targets, schizophrenia may evolve more comprehensive personalized approach, disorder's full spectrum symptoms improving patient quality life.

Язык: Английский

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Intergenerational transmission of complex traits and the offspring methylome

Molecular Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 3, 2025

Abstract The genetic makeup of parents can directly or indirectly affect their offspring phenome through transmission via the environment that is influenced by parental heritable traits. Our understanding mechanisms which indirect effects operate limited. Here, we hypothesize one mechanism methylome. To test this hypothesis, polygenic scores (PGSs) for schizophrenia, smoking initiation, educational attainment (EA), social deprivation, body mass index (BMI), and height were analyzed in a cohort 1528 (51.5% boys, mean [ SD ] age = 10 [2.8] years). We modelled parent PGSs on buccal-DNA methylation, accounting own PGS offspring, found significant associations between EA, BMI, height, buccal methylation sites, comprising 16, 2, 1, 6 respectively (alpha 2.7 × −5 ). More DNA sites associated with maternal than paternal PGSs, possibly reflecting pre- periconceptional stronger involvement shaping offspring’s during early childhood.

Язык: Английский

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An Honest Reckoning With the Amygdala and Mental Illness

American Journal of Psychiatry, Год журнала: 2024, Номер 181(12), С. 1059 - 1075

Опубликована: Дек. 1, 2024

Anxiety disorders are a leading source of human misery, morbidity, and premature mortality. Existing treatments far from curative for many, underscoring the need to clarify underlying neural mechanisms. Although many brain regions contribute, amygdala has received most intense scientific attention. Over past several decades, this scrutiny yielded detailed understanding function, but it failed produce new clinical assays, biomarkers, or cures. Rising urgent public health challenge demands an honest reckoning with functional-neuroanatomical complexity shift theories anchored on "the amygdala" models centered specific nuclei cell types. This review begins by examining evidence studies rodents, monkeys, humans "canonical model," idea that plays central role in fear- anxiety-related states, traits, disorders. Next, authors selectively highlight work indicating canonical model, while true, is overly simplistic fails adequately capture actual state evidentiary record, breadth amygdala-associated functions illnesses, amygdala's functional architecture. The describe implications these facts basic neuroimaging research. concludes some general recommendations grappling accelerating efforts understand more effectively treat amygdala-related psychopathology.

Язык: Английский

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Genetic Diversity in Schizophrenia: Developmental Implications of Ultra-Rare, Protein-Truncating Mutations

Genes, Год журнала: 2024, Номер 15(9), С. 1214 - 1214

Опубликована: Сен. 17, 2024

The genetic basis of schizophrenia (SZ) remains elusive despite its characterization as a highly heritable disorder. This incomplete understanding has led to stagnation in therapeutics and treatment, leaving many suffering with insufficient relief from symptoms. However, recent large-cohort genome- exome-wide association studies have provided insights into the underlying machinery. scale these allows for identification ultra-rare mutations that confer substantial disease risk, guiding clinicians researchers toward general classes genes are central SZ etiology. One such large-scale collaboration effort by Schizophrenia Exome Sequencing Meta-Analysis consortium identified ten, high-risk, ultra-rare, protein-truncating variants, providing clearest picture date dysfunctional gene products substantially increase risk SZ. While provide valuable information regarding "what" linked disorder, it is an open question "when" during brain development impose deleterious effects. To shed light on this unresolved aspect etiology, we queried BrainSpan developmental mRNA expression database ten high-risk discovered three trajectories throughout pre- postnatal development. elusiveness infer, not only borne out heterogeneity across clinical cases, but also our how perturb neurodevelopment multiple critical periods. We contextualize notion within National Institute Mental Health's Research Domain Criteria framework emphasize utility considering both variables context future studies.

Язык: Английский

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Perinatal Hypoxia and Immune System Activation in Schizophrenia Pathogenesis: Critical Considerations During COVID-19 Pandemic

Physiological Research, Год журнала: 2024, Номер unknown, С. S615 - S639

Опубликована: Ноя. 22, 2024

Schizophrenia, a severe psychiatric, neurodevelopmental disorder affecting about 0.29-1 % of the global population, is characterized by hallucinations, delusions, cognitive impairments, disorganized thoughts and speech, leading to significant social withdrawal emotional blunting. During 1980s, considerations diseases that result from complex interactions genetic background environmental factors started appear. One critical times vulnerability perinatal period. Concerning schizophrenia, obstetric complications are associated with hypoxia fetus or neonate were identified as risk. Also, maternal infections during pregnancy linked schizophrenia epidemiological, serologic studies. Research efforts then led development experimental models testing impact immune activation on disorders. These usually studied separately, but given now validated, it feasible investigate both together. Inclusion additional factors, such metabolic disturbances chronic stress, may need be considered also. Understanding interplay in schizophrenia's etiology crucial for developing targeted prevention therapeutic strategies.

Язык: Английский

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Intergenerational transmission of complex traits and the offspring methylome

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

Опубликована: Апрель 16, 2024

Abstract The genetic makeup of parents can directly or indirectly affect their offspring phenome through transmission via the environment that is influenced by parental heritable traits. Our understanding mechanisms which indirect effects operate limited. Here, we hypothesize one mechanism methylome. To test this hypothesis, polygenic scores (PGSs) for schizophrenia, smoking initiation, educational attainment (EA), social deprivation, body mass index (BMI), and height were analyzed in a cohort 1,528 (51.5% boys, mean [ SD ] age = 10 [2.8] years). We modelled parent PGSs on buccal-DNA methylation, accounting own PGS offspring, found significant associations between EA, BMI, height, buccal methylation sites, comprising 16, 2, 1, 6 respectively (alpha 2.7 × −5 ). More DNA sites associated with maternal than paternal PGSs, possibly reflecting pre- periconceptional stronger involvement shaping offspring’s during early childhood.

Язык: Английский

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A general principle governing neuronal evolution reveals a human-accelerated neuron type potentially underlying the high prevalence of autism in humans

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

Опубликована: Авг. 3, 2024

The remarkable ability of a single genome sequence to encode diverse collection distinct cell types, including the thousands types found in mammalian brain, is key characteristic multicellular life. While it has been observed that some are far more evolutionarily conserved than others, factors driving these differences evolutionary rate remain unknown. Here, we hypothesized highly abundant neuronal may be under greater selective constraint rarer leading variation their rates evolution. To test this, leveraged recently published cross-species single-nucleus RNA-sequencing datasets from three regions neocortex. We strikingly consistent relationship where subtypes show gene expression conservation between species, which replicated across independent covering >10

Язык: Английский

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