Hyperuricemia and its related diseases: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 28, 2024

Abstract Hyperuricemia, characterized by elevated levels of serum uric acid (SUA), is linked to a spectrum commodities such as gout, cardiovascular diseases, renal disorders, metabolic syndrome, and diabetes, etc. Significantly impairing the quality life for those affected, prevalence hyperuricemia an upward trend globally, especially in most developed countries. UA possesses multifaceted role, antioxidant, pro-oxidative, pro-inflammatory, nitric oxide modulating, anti-aging, immune effects, which are significant both physiological pathological contexts. The equilibrium circulating urate hinges on interplay between production excretion, delicate balance orchestrated transporter functions across various epithelial tissues cell types. While existing research has identified involvement numerous biological processes signaling pathways, precise mechanisms connecting disease etiology remain be fully elucidated. In addition, influence genetic susceptibilities environmental determinants calls detailed nuanced examination. This review compiles data from global epidemiological studies clinical practices, exploring foundations transporters depth. Furthermore, we uncover complex induced inflammation influences individuals with association its relative disease, offering foundation innovative therapeutic approaches advanced pharmacological strategies.

Language: Английский

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Pervasive Downward Bias in Estimates of Liability-Scale Heritability in Genome-wide Association Study Meta-analysis: A Simple Solution

Biological Psychiatry, Journal Year: 2022, Volume and Issue: 93(1), P. 29 - 36

Published: June 8, 2022

Language: Английский

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Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation

American Journal of Psychiatry, Journal Year: 2022, Volume and Issue: 179(11), P. 833 - 843

Published: Sept. 7, 2022

Objective: Mental disorders are heritable and polygenic, genome-wide genetic correlations (rg) have indicated widespread shared risk across multiple related traits, mirroring their overlapping clinical characteristics. However, rg may underestimate the underpinnings of mental traits because it does not differentiate mixtures concordant discordant effects from an absence overlap. Using novel statistical genetics tools, authors aimed to evaluate overlap between when accounting for mixed effect directions. Methods: The applied bivariate causal mixture model (MiXeR) summary statistics four disorders, height association studies (Ns ranged 53,293 766,345). MiXeR estimated number “causal” variants a given trait (“polygenicity”), correlation (rgs). Local was investigated using LAVA. Results: Among ADHD least polygenic (5.6K variants), followed by bipolar disorder (8.6K), schizophrenia (9.6K), depression (14.5K). Most were (4.4K–9.3K) (5.2K–12.8K), but with disorder-specific variations in rgs. Overlap small (0.7K–1.1K). estimates correlated LAVA local (r=0.88, p<0.001). Conclusions: There is extensive directions few variants. This suggests that predominantly differentiated divergent distributions pleiotropic rather than represents conceptual advance our understanding landscape architecture which inform discovery, biological characterization, nosology, prediction.

Language: Английский

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PRSet: Pathway-based polygenic risk score analyses and software

PLoS Genetics, Journal Year: 2023, Volume and Issue: 19(2), P. e1010624 - e1010624

Published: Feb. 7, 2023

Polygenic risk scores (PRSs) have been among the leading advances in biomedicine recent years. As a proxy of genetic liability, PRSs are utilised across multiple fields and applications. While numerous statistical machine learning methods developed to optimise their predictive accuracy, these typically distil liability single number based on aggregation an individual’s genome-wide alleles. This results key loss information about profile, which could be critical given functional sub-structure genome heterogeneity complex disease. In this manuscript, we introduce ‘pathway polygenic’ paradigm disease risk, liabilities underlie diseases, rather than liability. We describe method accompanying software, PRSet, for computing analysing pathway-based PRSs, polygenic calculated genomic pathways each individual. evaluate potential pathway two distinct ways, creating major sections: (1) first section, benchmark PRSet as enrichment tool, evaluating its capacity capture GWAS signal pathways. find that target sample sizes >10,000 individuals, similar power MAGMA LD score regression, with advantage providing individual-level estimates -opening up range PRS applications, (2) second performance stratification. show using supervised stratification approach, (computed by PRSet) outperform standard C+T lassosum) classifying subtypes 20 21 scenarios tested. definition annotation becomes increasingly refined, expect offer insights into treatment response, generate biologically tractable therapeutic targets from signal, and, ultimately, provide powerful path precision medicine.

Language: Английский

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Diagnosis and management of bipolar disorders

BMJ, Journal Year: 2023, Volume and Issue: unknown, P. e073591 - e073591

Published: April 12, 2023

Abstract Bipolar disorders (BDs) are recurrent and sometimes chronic of mood that affect around 2% the world’s population encompass a spectrum between severe elevated excitable states (mania) to dysphoria, low energy, despondency depressive episodes. The illness commonly starts in young adults is leading cause disability premature mortality. clinical manifestations bipolar disorder can be markedly varied within individuals across their lifespan. Early diagnosis challenging misdiagnoses frequent, potentially resulting missed early intervention increasing risk iatrogenic harm. Over 15 approved treatments exist for various phases disorder, but outcomes often suboptimal owing insufficient efficacy, side effects, or lack availability. Lithium, first treatment continues most effective drug overall, although full remission only seen subset patients. Newer atypical antipsychotics increasingly being found depression; however, long term tolerability safety uncertain. For many with combination therapy adjunctive psychotherapy might necessary treat symptoms different illness. Several classes medications treating predicting which medication likely tolerable not yet possible. As pathophysiological insights into causes revealed, new era targeted aimed at causal mechanisms, they pharmacological psychosocial, will hopefully developed. time being, judgment, shared decision making, empirical follow-up remain essential elements care. This review provides an overview features, diagnostic subtypes, major modalities available people highlighting recent advances ongoing therapeutic challenges.

Language: Английский

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Machine learning dissection of human accelerated regions in primate neurodevelopment

Neuron, Journal Year: 2023, Volume and Issue: 111(6), P. 857 - 873.e8

Published: Jan. 13, 2023

Using machine learning (ML), we interrogated the function of all human-chimpanzee variants in 2,645 human accelerated regions (HARs), finding 43% HARs have with large opposing effects on chromatin state and 14% neurodevelopmental enhancer activity. This pattern, consistent compensatory evolution, was confirmed using massively parallel reporter assays chimpanzee neural progenitor cells. The species-specific activity accurately predicted from presence absence transcription factor footprints each species. Despite these striking cis effects, a given HAR sequence nearly identical suggests that did not evolve to compensate for changes trans environment but instead altered their ability bind factors present both Thus, ML prioritized functional neurodevelopment revealed an unexpected reason why may evolved so rapidly.

Language: Английский

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Multi-omic profiling of the developing human cerebral cortex at the single-cell level

Science Advances, Journal Year: 2023, Volume and Issue: 9(41)

Published: Oct. 12, 2023

The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that mediated, part, by spatiotemporal activity cis-regulatory elements (CREs). We simultaneously profiled and chromatin accessibility 45,549 cortical nuclei across six broad developmental time points from fetus to adult. identified cell type-specific domains which highly correlated with expression. Differentiation pseudotime trajectory analysis indicates at CREs precedes transcription structure play a critical role neuronal lineage commitment. In addition, we mapped temporally specific genetic loci implicated neuropsychiatric traits, including schizophrenia bipolar disorder. Together, our results describe complex regulation composition stages determination shed light on impact alterations disease.

Language: Английский

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A concerted neuron–astrocyte program declines in ageing and schizophrenia

Nature, Journal Year: 2024, Volume and Issue: 627(8004), P. 604 - 611

Published: March 6, 2024

Abstract Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people’s cortical neurons astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22–97 years, including healthy individuals with schizophrenia. Latent-factor analysis these data revealed that, whose more strongly expressed genes encoding synaptic components, astrocytes distinct functions for synthesizing cholesterol, an astrocyte-supplied component membranes. call this neuron astrocyte program (SNAP). In schizophrenia ageing—two conditions that involve declines cognitive flexibility plasticity 1,2 —cells divested from SNAP: astrocytes, glutamatergic (excitatory) GABAergic (inhibitory) all showed reduced SNAP expression corresponding degrees. The astrocytic neuronal components both involved which genetic risk factors were concentrated. SNAP, varies quantitatively even among similar age, may underlie many aspects normal interindividual differences be important point convergence multiple kinds pathophysiology.

Language: Английский

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Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 792 - 808

Published: April 18, 2024

Language: Английский

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Multi-ancestry meta-analysis and fine-mapping in Alzheimer’s disease

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(7), P. 3121 - 3132

Published: May 18, 2023

Abstract Genome-wide association studies (GWAS) of Alzheimer’s disease are predominantly carried out in European ancestry individuals despite the known variation genetic architecture and prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, African American populations, an additional a Caribbean Hispanic population using previously reported genotype data to perform largest multi-ancestry meta-analysis related dementias date. This method allowed us identify two independent novel disease-associated loci on chromosome 3. also diverse haplotype structures fine-map nine with posterior probability >0.8 globally assessed heterogeneity risk factors Additionally, we compared generalizability multi-ancestry- single-ancestry-derived polygenic scores three-way admixed Colombian population. Our findings highlight importance representation uncovering understanding putative that contribute dementias.

Language: Английский

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