Causal relationship between gut microbiota and ageing: A multi-omics Mendelian randomization study

Archives of Gerontology and Geriatrics, Год журнала: 2025, Номер 131, С. 105765 - 105765

Опубликована: Янв. 20, 2025

Язык: Английский

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A metabolomic profile of biological aging in 250,341 individuals from the UK Biobank

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 15, 2024

Язык: Английский

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Body Fat Distribution and Ectopic Fat Accumulation as Mediator of Diabetogenic Action of Lipid-Modifying Drugs

Mayo Clinic Proceedings, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Genetically supported targets and drug repurposing for brain aging: A systematic study in the UK Biobank

Science Advances, Год журнала: 2025, Номер 11(11)

Опубликована: Март 12, 2025

Brain age gap (BAG), the deviation between estimated brain and chronological age, is a promising marker of health. However, genetic architecture reliable targets for aging remains poorly understood. In this study, we estimate magnetic resonance imaging (MRI)–based using deep learning models trained on UK Biobank validated with three external datasets. A genome-wide association study BAG identified two unreported loci seven previously reported loci. By integrating Mendelian Randomization (MR) colocalization analysis eQTL pQTL data, prioritized genetically supported druggable genes, including MAPT , TNFSF12 GZMB SIRPB1 GNLY NMB C1RL as aging. We rediscovered 13 potential drugs evidence from clinical trials several strong support. Our provides insights into basis aging, potentially facilitating drug development to extend health span.

Язык: Английский

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Mendelian randomization evidence for the causal effect of mental well-being on healthy aging

Nature Human Behaviour, Год журнала: 2024, Номер 8(9), С. 1798 - 1809

Опубликована: Июнь 17, 2024

Язык: Английский

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Identifying novel risk genes in intracranial aneurysm by integrating human proteomes and genetics

Brain, Год журнала: 2024, Номер 147(8), С. 2817 - 2825

Опубликована: Авг. 1, 2024

Abstract Genome-wide association studies (GWAS) have become increasingly popular for detecting numerous loci associated with intracranial aneurysm (IA), but how these function remains unclear. In this study, we employed an integrative analytical pipeline to efficiently transform genetic associations and identify novel genes IA. Using multidimensional high-throughput data, integrated proteome-wide (PWAS), transcriptome-wide (TWAS), Mendelian randomization (MR) Bayesian co-localization analyses prioritize that can increase IA risk by altering their expression protein abundances in the brain blood. Moreover, single-cell RNA sequencing (scRNA-seq) of circle Willis was performed enrich filtered cells, gene set enrichment analysis (GSEA) conducted each using bulk RNA-seq data No significant cis-regulated plasma levels were proven be The five found According cellular analysis, expressed mainly endothelium, fibroblasts vascular smooth muscle cells. Only three genes, CNNM2, GPRIN3 UFL1, passed MR analyses. While UFL1 not validated confirmation PWAS as it profiled, TWAS. GSEA suggested are cell cycle. addition, abundance CNNM2 rupture (based on PWAS, analyses). Our findings indicated (CNNM2 correlated rupture) potential may provide a broad hint future research possible mechanisms therapeutic targets

Язык: Английский

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Cross-trait multivariate GWAS confirms health implications of pubertal timing

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 18, 2025

Pubertal timing is highly variable and associated with long-term health outcomes. Phenotypes pubertal include age at menarche, voice break, first facial hair growth spurt, seems to have a shared genetic architecture between the sexes. However, puberty phenotypes primarily been assessed separately, failing account for genetics, which limits reliability of purported implications. Here, we model common using multivariate GWAS, an effective population 514,750 European participants. We find 266 independent variants in 197 loci, including 18 novel variants. Transcriptomic, proteome imputation fine-mapping analyses reveal genes causal timing, KDM4C, LEPR, CCNC, ACP1, PCSK1. Linkage disequilibrium score regression Mendelian randomisation analysis establish associations earlier both accelerated ageing risk developing cardiovascular disease osteoporosis. that alanine aminotransferase, glycated haemoglobin, high-density lipoprotein cholesterol Parabacteroides levels are mediators these relationships, controlling oily fish retinol intake may be beneficial promoting healthy development.

Язык: Английский

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Novel mechanistic insights into the comorbidity of anemia and rheumatoid arthritis: Identification of therapeutic targets

Molecular Immunology, Год журнала: 2025, Номер 180, С. 74 - 85

Опубликована: Фев. 27, 2025

Язык: Английский

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Exploring the neural mechanisms linking healthy aging and cognitive maintenance: insights from Mendelian randomization and mediation analyses

Cerebral Cortex, Год журнала: 2025, Номер 35(3)

Опубликована: Март 1, 2025

Abstract As global population ages, maintaining cognitive health in elderly is crucial. Previous studies suggest a positive link between healthy aging and cognition, but the neural mechanisms remain unclear. This study used genome-wide association studydata to investigate cognition. We employed 2-sample Mendelian randomization evaluate causal relationship (indexed by multivariate genetic predictor, mvAge) 6 measurements. then 2-step approach mediation analysis identify brain imaging-derived phenotypes potentially mediating this relationship. indicated that had with various functions (common executive function, intelligence, performance, fluid intelligence score). Two-step identified 27 having robust relationships Mediation suggested volume of subcallosal cortex might mediate effects on all 4 functions. Volume cerebellum’s VIIb could common functions, while fractional anisotropy anterior thalamic radiation performance. These findings specific regions may play potential role maintenance.

Язык: Английский

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Bayesian estimation of shared polygenicity identifies drug targets and repurposable medicines for human complex diseases

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

Опубликована: Март 17, 2025

Abstract Background Complex diseases may share portions of their polygenic architectures which can be leveraged to identify drug targets with low off-target potential or repurposable candidates. However, the literature lacks methods make these inferences at scale using publicly available data. Methods We introduce a Bayesian model estimate structure trait only gene-based association test statistics from GWAS summary data and returns gene-level posterior risk probabilities (PRPs). PRPs were used infer shared polygenicity between 496 pairs we measures that prioritize effects repurposing potential. Results Across 32 traits, estimated 69.5 97.5% disease-associated genes are multiple number druggable associated single disease ranged 1 (multiple sclerosis) 59 (schizophrenia). Estimating genetic architecture ALS all other traits identified KIT gene as potentially harmful target because its deleterious triglycerides, but also TBK1 SCN11B putatively safer non-association any 31 traits. additionally found 21 candidate repourposable for Alzheimer’s (AD) (e.g., PLEKHA1, PPIB ) 5 GAK, DGKQ ). Conclusions The sets have limited generally smaller compared pleiotropic targets, both represent promising directions future experimental studies.

Язык: Английский

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