Treatment resistance NMDA receptor pathway polygenic score is associated with brain glutamate in schizophrenia DOI Creative Commons
Kira Griffiths, Sophie E Smart, Gareth J. Barker

и другие.

Schizophrenia Research, Год журнала: 2023, Номер 260, С. 152 - 159

Опубликована: Авг. 30, 2023

Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology schizophrenia and may be particularly relevant severe, treatment-resistant symptoms. The underlying mechanism involve hypofunction NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed genetic variants within receptor encoding genes, are associated with cortical schizophrenia. Anterior cingulate cortex (ACC) was measured 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy (1H-MRS). Two gene sets were sourced from Molecular Signatories Database scores constructed PRSet. weighted by single nucleotide polymorphism (SNP) associations schizophrenia, ACC tested. then tested SNPs non-treatment-resistant glutamate. A higher complex score significantly lower (β = −0.25, 95 % CI −0.49, −0.02, competitive p 0.03). When there no association between 0.05, −0.18, 0.27, 0.79). These results provide initial evidence an common variation function levels This specific to when SNP

Язык: Английский

Unraveling the intercellular communication disruption and key pathways in Alzheimer’s disease: an integrative study of single-nucleus transcriptomes and genetic association DOI Creative Commons
Andi Liu, Brisa S. Fernandes, Citu Citu

и другие.

Alzheimer s Research & Therapy, Год журнала: 2024, Номер 16(1)

Опубликована: Янв. 2, 2024

Recently, single-nucleus RNA-seq (snRNA-seq) analyses have revealed important cellular and functional features of Alzheimer's disease (AD), a prevalent neurodegenerative disease. However, our knowledge regarding intercellular communication mediated by dysregulated ligand-receptor (LR) interactions remains very limited in AD brains.

Язык: Английский

Процитировано

14
Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures DOI Creative Commons
Tiit Örd, Tapio Lönnberg,

Valtteri Nurminen

и другие.

The American Journal of Human Genetics, Год журнала: 2023, Номер 110(5), С. 722 - 740

Опубликована: Апрель 14, 2023

Coronary artery disease (CAD) is a pandemic where up to half of the risk explained by genetic factors. Advanced insights into basis CAD require deeper understanding contributions different cell types, molecular pathways, and genes heritability. Here, we investigate biological diversity atherosclerosis-associated states interrogate their contribution using single-cell bulk RNA sequencing (RNA-seq) mouse human lesions. We identified 12 disease-associated that characterized further gene set functional profiling, ligand-receptor prediction, transcription factor inference. Importantly, Vcam1+ smooth muscle state contributed most SNP-based heritability CAD. In line with this, variants near regulatory elements largest fraction CAD-risk variance between individuals. Using this information for variant prioritization, derived hybrid polygenic score (PRS) demonstrated improved performance over classical PRS. Our results provide mechanisms associated risk, which could make promising precision medicine tailored therapeutic interventions in future.

Язык: Английский

Процитировано

23
Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease DOI Creative Commons
Hyun‐Sik Yang,

Ling Teng,

Daniel W. Kang

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 30, 2023

Many of the Alzheimer's disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how when genetic localizing to these cell types contributes AD pathophysiology remains unclear. Here, we derive cell-type-specific polygenic scores (ADPRS) from two extensively characterized datasets uncover impact on endophenotypes. In an autopsy dataset spanning all stages (n = 1457), astrocytic ADPRS affected diffuse neuritic plaques (amyloid-β), while microglial plaques, activation, neurofibrillary tangles (tau), cognitive decline. independent neuroimaging cognitively unimpaired elderly 2921), was associated with amyloid-β, amyloid-β tau, connecting pathology even before symptom onset. Together, our study provides human evidence implicating multiple glial pathophysiology, starting preclinical stage.

Язык: Английский

Процитировано

21
Deep representation learning for clustering longitudinal survival data from electronic health records DOI Creative Commons
Jiajun Qiu,

Yao Hu,

Li Li

и другие.

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

Опубликована: Март 14, 2025

Язык: Английский

Процитировано

1
Research Review: A guide to computing and implementing polygenic scores in developmental research DOI
Andrea G. Allegrini, Jessie R. Baldwin, Wikus Barkhuizen

и другие.

Journal of Child Psychology and Psychiatry, Год журнала: 2022, Номер 63(10), С. 1111 - 1124

Опубликована: Март 30, 2022

The increasing availability of genotype data in longitudinal population‐ and family‐based samples provides opportunities for using polygenic scores (PGS) to study developmental questions child adolescent psychology psychiatry. Here, we aim provide a comprehensive overview how PGS can be generated implemented psycho(patho)logy, with focus on designs. As such, the paper is organized into three parts: First, formal definition related concepts, focusing assumptions limitations. Second, give general methods used compute scores, ranging from classic approach more advanced methods. We include recommendations reference resources available researchers aiming conduct analyses. Finally, practical applications analysis data. describe have been research outcomes, they applied address questions.

Язык: Английский

Процитировано

24
Machine learning nominates the inositol pathway and novel genes in Parkinson’s disease DOI Creative Commons
Eric Yu, Roxanne Larivière, Rhalena A. Thomas

и другие.

Brain, Год журнала: 2023, Номер 147(3), С. 887 - 899

Опубликована: Окт. 6, 2023

Abstract There are 78 loci associated with Parkinson’s disease in the most recent genome-wide association study (GWAS), yet specific genes driving these associations mostly unknown. Herein, we aimed to nominate top candidate gene from each locus and identify variants pathways potentially involved disease. We trained a machine learning model predict disease-associated GWAS using genomic, transcriptomic epigenomic data brain tissues dopaminergic neurons. nominated identified novel disease, such as inositol phosphate biosynthetic pathway (INPP5F, IP6K2, ITPKB PPIP5K2). Specific common coding SPNS1 MLX may be burden tests of rare further support that CNIP3, LSM7, NUCKS1 polyol/inositol Functional studies needed analyse involvements

Язык: Английский

Процитировано

17
An investigation on the alterations in Wnt signaling in ADHD across developmental stages DOI Creative Commons

Natalie Monet Walter,

Cristine Marie Yde Ohki,

Michelle Rickli

и другие.

Neuroscience Applied, Год журнала: 2024, Номер 3, С. 104070 - 104070

Опубликована: Янв. 1, 2024

The canonical Wnt signaling pathway plays a vital role in the developmental processes of Central Nervous System throughout both prenatal and postnatal stages, as well maintaining homeostasis during adulthood. Its complex intracellular cascade involves participation key proteins (i.e., GSK3β β-catenin) to activate transcription target genes. These genes subsequently control like cell proliferation, maturation, determination fate. Previous studies suggest that this can also be associated with Attention-Deficit Hyperactivity Disorder (ADHD), neurodevelopmental disorder multifactorial etiology. This study aimed clarify if at what stage is altered ADHD. Accordingly, we carried out proteomic functional assessments using Western Blot reporter assays, respectively. were performed induced pluripotent stem (iPSC), neural (NSC), neuronal phases. IPSCs generated from somatic cells retrieved 5 controls patients diagnosed As opposed iPSCs, ADHD NSCs showed alterations protein expression β-catenin, suggesting increased activity group. Moreover, assays confirmed higher NSCs. Our molecular findings correlated genetic predisposition clinical traits displayed by their respective donors. In conclusion, these results crucial cellular disrupted patient-specific NSCs, potentially explaining deficits clinically exhibited patients.

Язык: Английский

Процитировано

6
Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non‐demented individuals DOI Creative Commons
Luigi Lorenzini,

Lyduine E. Collij,

Niccolò Tesi

и другие.

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(9), С. 6146 - 6160

Опубликована: Июль 29, 2024

Abstract INTRODUCTION Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, a key step toward precision medicine. METHODS We computed pathway‐specific scores (GRSs) in non‐demented individuals investigated AD variants predict cerebrospinal fluid (CSF) imaging biomarkers reflecting pathology, cardiovascular, white matter integrity, brain connectivity. RESULTS CSF amyloidbeta phosphorylated tau were most GRSs. Inflammatory pathways associated with cerebrovascular disease, whereas quantitative measures of lesion microstructure integrity predicted by clearance migration pathways. Functional connectivity alterations involved signal transduction synaptic communication. DISCUSSION This study reveals distinct profiles association pathophysiological aspects predementia stages AD, unraveling the substrates heterogeneity AD‐associated endophenotypes promoting forward understanding development personalized therapies. Highlights Polygenic for encompasses six that can be quantified scores, differentially relate biomarkers. are mostly burden. White health membrane functional communication

Язык: Английский

Процитировано

5
The utility of obesity polygenic risk scores from research to clinical practice: A review DOI Creative Commons
Philip R. Jansen, Niels Vos,

Jorrit van Uhm

и другие.

Obesity Reviews, Год журнала: 2024, Номер 25(11)

Опубликована: Июль 29, 2024

Summary Obesity represents a major public health emergency worldwide, and its etiology is shaped by complex interplay of environmental genetic factors. Over the last decade, polygenic risk scores (PRS) have emerged as promising tool to quantify an individual's obesity. The field PRS in obesity genetics rapidly evolving, shedding new lights on mechanisms holding promise for contributing personalized prevention treatment. Challenges persist terms clinical integration, including need further validation large‐scale prospective cohorts, ethical considerations, implications disparities. In this review, we provide comprehensive overview studying obesity, spanning from methodological nuances applications challenges. We summarize latest developments generation refinement advances methodologies aggregating genome‐wide association study data improving predictive accuracy, discuss limitations that be overcome fully realize potential benefits both medicine health.

Язык: Английский

Процитировано

5
Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis DOI Creative Commons
Tracy L. Warren, Justin D. Tubbs, Tyler A. Lesh

и другие.

Molecular Psychiatry, Год журнала: 2024, Номер 29(8), С. 2389 - 2398

Опубликована: Март 15, 2024

A primary goal of psychiatry is to better understand the pathways that link genetic risk psychiatric symptoms. Here, we tested association diagnosis and endophenotypes with overall neurotransmitter pathway-specific polygenic in patients early-stage psychosis. Subjects included 205 demographically diverse cases a psychotic disorder who underwent comprehensive neurological phenotyping 115 matched controls. Following genotyping, calculated scores (PGSs) for schizophrenia (SZ) bipolar (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if can be partitioned into affected pathways, pathway PGSs (pPGSs) SZ affecting each four major systems: glutamate, GABA, dopamine, serotonin. Psychosis subjects had elevated PGS versus controls; or BP diagnoses stronger risk, respectively. There was no significant within psychosis between individual symptom measures PGS. However, neurotransmitter-specific pPGSs were moderately associated specific endophenotypes; notably, glutamate deficits cognitive control during task-based fMRI, while dopamine global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups separated on positive symptoms, negative functioning, control. All clusters showed strong genome-wide risk. Cluster 2, characterized by additionally concentrated glutamatergic GABAergic pathways. Due intensive characterization our subjects, present study limited relatively small cohort. As such, results should followed up additional research at population mechanism level. Our suggests pathway-based analysis may powerful path forward mechanisms driving endophenotypes.

Язык: Английский

Процитировано

4