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Single-cell RNA sequencing and Mendelian randomization, revealing molecular mechanisms and causal correlation of immune-related genes in periodontitis.

The immune system has been linked to periodontitis risk in oral inflammation and systemic consequences. Specifically, this study investigated whether hub genes were associated with immune cells via integrating single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR). We analyzed scRNA-seq data to identify differentially expressed genes (DEGs) and immune cell subtypes in periodontitis. First, MR analysis was conducted using eQTL data to determine causal relationships between immune cell gene expression and periodontitis risk. Then, Gene ontology (GO) and pathway enrichment analys

Precision Target Discovery for Migraine: An Integrated GWAS-eQTL-PheWAS Pipeline.

Migraine is a complex neurological disorder that severely compromises quality of life. Current therapies remain inadequate, creating an urgent need for precision medicine approaches. To bridge this gap, we integrated genome-wide association studies (GWASs) and multi-tissue expression quantitative trait loci (eQTL) data. Using Mendelian randomization (SMR/HEIDI) to identify putatively causal genes, followed by colocalization analysis, protein-protein interaction networks, and gene enrichment, we prioritized druggable targets. Phenome-wide association studies (PheWASs) further assessed their pot…

Allelic variations and interactive feedback in major regulators of plant architecture confer high-altitude adaptation in Arabidopsis thaliana.

Ideal plant architectures are crucial for adapting to environmental changes, yet the molecular mechanisms behind high-altitude plant adaptations remain elusive. We characterized the dwarf and highly branched traits of the Tibet ecotype of Arabidopsis thaliana (L.) Heynh. Quantitative trait locus (QTL) analysis revealed that GA5 and BRC1, as major genes regulating plant height and branching, respectively, underlie the variation in plant architecture of the Tibet ecotype. Loss-of-function of GA5 disrupts gibberellin biosynthesis, leading to dwarfism, and natural variations in the BRC1 promoter r

Association between interleukin-12 p40 subunit and risk of primary Sjögren's disease: a Mendelian randomization study.

OBJECTIVES: IL-12 signalling was proposed in the immunopathogenesis of primary Sjögren's disease. The efficacy of therapies targeting this pathway is currently unclear. Herein, we investigated the associations between circulating proteins involved in the IL-12 and IL-23 signalling pathways on primary Sjögren's disease using Mendelian randomization. METHODS: We selected single nucleotide polymorphisms from protein quantitative trait loci of IL12A, IL12B, IL12Rβ1, IL12Rβ2 and IL23R to examine the association between alterations in their levels and risk of primary Sjögren's disease. Genetic asso…

Integrating multi-omics to reveal the causal effect of gut microbiota on post-traumatic stress disorder and potential drug target analysis.

Background: Observational evidence indicates genetic factors influence both gut microbiota composition and post-traumatic stress disorder (PTSD) susceptibility. But robust common variants have not been identified. This study aimed to investigate the common genetic variant loci and potential drug targets between the gut microbiota and PTSD.Methods: Based on public databases, we conducted a genome-wide association analysis (GWAS) of 207 microbial taxa and 205 pathways. Causal relationships were established through bidirectional Mendelian randomization (MR) and Bayesian weighted mendelian randomi

Deciphering tissue-specific protein regulation for insights into cardiometabolic disease.

Understanding tissue-specific mechanisms of protein regulation gives crucial insights into cardiometabolic disease and informs drug discovery. Most proteomic studies have primarily concentrated on plasma, overlooking tissue-specific effects. Utilizing Olink technology, we assessed relative protein levels across plasma and tissue (aortic wall, mammary artery, liver, and skeletal muscle) from the STARNET cohort: 284 individuals with a high prevalence of coronary artery disease (CAD). We identified 608 cis protein quantitative trait loci (pQTLs), primarily in plasma, reflecting greater protein va…

Remarkable heterogeneity revealed in the genetic architecture of resistance to a key bacterial pathogen in two commercial rainbow trout populations.

BACKGROUND: Bacterial cold-water disease (BCWD), caused by Flavobacterium psychrophilum, remains a major challenge for rainbow trout (Oncorh … sparse linear mixed model (BSLMM), separately in each population and in a combined dataset. Eleven quantitative trait loci (QTLs) were identified across the analyses, with limited overlap between populations, highlighting the complexity and partial divergence of resistance architectures. Several candidate genes located within QTL regions were involved in immune signalli …

Identification of therapeutic targets for chronic kidney disease through Mendelian randomization analysis of druggable genes.

Chronic Kidney Disease (CKD) is a multifaceted and gradually advancing condition characterized by a complex pathogenesis. The current therapeutic options for CKD remain limited in efficacy. Consequently, the identification and exploration of novel drug targets for CKD are of paramount importance. We identified cis-expression quantitative trait loci (cis-eQTLs) with potential as drug targets from the eQTLGen Consortium database to serve as the exposure. For the outcome, we utilized a genome-wide association study (GWAS) of chronic kidney disease (CKD) from the FinnGen database, which comprised …

[Relationship between sterol carrier protein 2 gene and prostate cancer: Based on single-cell RNA sequencing combined with Mendelian randomization].

Objective： To investigate the relationship between the lipid metabolism-related gene sterol carrier protein 2(SCP2) and prostate cancer (PCa … differential and trajectory analyses. Single nucleotide polymorphism (SNP) data for SCP2 expression quantitative trait loci (eQTL) were subsequently downloaded from Genotype-Tissue Expression (GTEx) and investigated from the PCa Society Cancer-Related Genomic Alteration Panel for the Investigation of Cancer-Related Alterations (PRACTICAL) to obtain PCa outcome data for M …

Metabolome-wide Mendelian randomisation reveals causal links between circulating metabolites and type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease that causes destruction of the insulin-producing pancreatic beta cell, resulting in high levels of blood glucose and profound alterations in carbohydrate, lipid, and protein metabolism if untreated. We aimed to identify if circulating metabolites are causally linked to risk of T1D, using two-sample Mendelian Randomisation (MR). METHODS: For our discovery and replication MR analyses, we used SNP-instruments for circulating metabolites measured in seven large GWAS in Europeans. The corresponding effects of the SNP-instruments on T1D wer

Alternatively spliced NFKB1 transcripts enriched in Andean Aymara modulate inflammation, HIF and hemoglobin.

The molecular basis of increased hemoglobin in Andean Aymara highlanders is unknown. We conducted an integrative analysis of whole-genome-sequencing and granulocytes transcriptomics from Aymara and Europeans in Bolivia to explore genetic basis of the Aymara high hemoglobin. Differentially expressed and spliced genes in Aymaras were associated with inflammatory and hypoxia-related pathways. We identified transcripts with 4th or 5th exon skipping of NFKB1 (AS-NFKB1), key part of NF-kB complex, and their splicing quantitative trait loci; these were increased in Aymaras. AS-NFKB1 transcripts corre…

Cross-tissue transcriptome-wide association studies identify genetic susceptibility genes for prostate cancer.

BACKGROUND: Despite significantPlease check if article title presented correctly. advances made by genome-wide association studies (GWAS) in … led that CASP10 (rs6735656), GGCX (rs2028900) may share genetic signals between GWAS and expression quantitative trait loci (eQTL), indicating common pathways in PCa pathogenesis. CONCLUSION: This study identified 13 new susceptibility genes significantly associated with PCa risk and provided new insights into the genetic basis of PCa, contributing to a more comprehensi …

Decoding rheumatoid arthritis: Biomarker identification and immune profiling via bioinformatics and Mendelian randomization.

Rheumatoid arthritis (RA) is a prevalent autoimmune disorder that significantly reduces quality of life and imposes a substantial burden on society. This study addresses the critical gaps in current diagnostic and therapeutic modalities by aiming to identify improved biomarkers and potential therapeutic targets. Using data from 2 gene expression omnibus databases, we executed a comprehensive differential gene expression analysis integrated with Mendelian randomization. This approach employed advanced bioinformatics tools to scrutinize expression quantitative trait loci (eQTLs) and RA genome-wi…

Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study.

OBJECTIVE: Gout is a common inflammatory arthritis and lipid metabolism plays a crucial role in urate and gout. Potential associations between urate and gout and lipid-lowering drugs have been revealed in observational studies. However, the effects of lipid-lowering drugs on urate and gout remain controversial. The aim of this study was to investigate the genetic association between lipid-lowering drugs and urate and gout. METHODS: In this study, two genetic proxies were employed to approximate lipid-lowering drug exposure: expression quantitative trait loci (eQTL) associated with drug-target…

Integrative evidence linking excessive daytime sleepiness, narcolepsy, and hypertension: insights from NHANES, Mendelian randomization, and proteomics.

BACKGROUND: This study aimed to explore associations and causality between excessive daytime sleepiness (EDS), narcolepsy, and hypertension. METHODS: Publicly available data from the National Health and Nutrition Examination Survey (NHANES), genome-wide association studies (GWAS), and protein quantitative trait locus (pQTL) data sets were used for analysis. Logistic regression models assessed the association between different frequencies of EDS and hypertension, and sex-stratified subgroup analyses were also performed. Bi-directional Mendelian randomization (MR) evaluated the causal effect of

Genetics-mediated regulation of intestinal gene expression on microbiome contributes to human disease heritability.

The gut microbiome plays fundamental roles in physiological and pathological processes, yet its interaction with host gene expression and contribution to disease remain underexplored. Here, we integrate the genetic regulatory maps of 116 microbial genera with gene expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) in three intestinal tissues to dissect host-microbiome interaction. We identify 6088, 5810, and 2398 gene-to-microbiome regulatory loci in the transverse colon, sigmoid colon, and ileum, respectively. Among these, 13.2% of genes show broad regulatory effects …

Integrating Multiomic Mendelian Randomization, Microarray, Single-Cell RNA Sequencing, and Spatial RNA Sequencing to Identify Potential Therapeutic Targets for Vitiligo.

Vitiligo is a chronic skin disorder characterized by the selective destruction of melanocytes. Current treatments, such as topical steroids, tacrolimus, systemic steroids, and phototherapy, often yield suboptimal efficacy, underscoring the urgent need for more effective therapeutic targets. To identify potential drug targets, we conducted multiomics Mendelian randomization analyses using quantitative trait loci data for 4479 druggable genes in combination with vitiligo GWAS data from the GWAS Catalog and the FinnGen consortium. Among these candidates, CTSS demonstrated the highest therapeutic …

Identification of specific brain cell types associated with the interplay between inflammatory bowel diseases and neuropsychiatric disorders by Cell-Stratified Mendelian Randomisation.

BACKGROUND: Inflammatory bowel disease (IBD) has been suggested to be associated with neuropsychiatric disorders, but the underlying mechanisms remain poorly understood. METHODS: We employed Cell-Stratified Mendelian Randomisation (csMR) to analyse genetic variants associated with IBD and their effects on neuropsychiatric disorders. We conducted two-sample MR analyses using the partitioned genetic variants and performed SuSiE co-localisation analysis to identify shared causal variants between GWAS traits and the single-cell eQTL data. We also examined the imaging-derived phenotypes (IDPs) to

NLRC5-Mediated Epigenetic and Proteomic Regulation of Microglial Panoptosis Drives Neuroinflammation in Multiple Sclerosis.

Microglial dysfunction contributes to multiple sclerosis (MS) pathogenesis, yet the link between epigenetic regulation and inflammatory cell … ation (MR) linked NLRC5 expression to proteomic targets using UK Biobank and deCODE Iceland protein quantitative trait loci (pQTLs). Methylation quantitative trait locus (mQTL) analysis assessed MS-associated CpG sites. Lipopolysaccharide (LPS)-treated BV2 microglial models were used to validate NLRC5-PANoptosome assembly via Western blot and immunofluorescence. NLRC5 wa …

Воздействие окисляющего стресса Gene Protein, экспрессии и метилирования ДНК на множественный склероз: многомерное исследование менделий.

СПРАВОЧНАЯ ИНФОРМАЦИЯ: Окисляющий стресс (ОС) связан с развитием множественного склероза (MS), однако причинно-следственная связь с точки зрения генетической патофизиологии остается неясной. Мы использовали менделианскую случайность (MR) и анализ совместной локализации для изучения взаимосвязи между генами ОС и MS с использованием комплексного подхода, основанного на мультиомике. МЕТОДЫ: Мы получили данные по результатам исследования, проведенного в рамках всей ассоциации по геному (GWAS) MS, из Международного консорциума по многоразовым склерозовым генетикам (этап обнаружения) и исследования

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… With the advent of large‐scale genomic studies and molecular quantitative trait loci (QTL) data, it is now feasible to explore the mechanisms regulating OS‐related genes in MS through analyses of methylation, gene expression, and protein levels. … Additionally, the expression quantitative trait loci (eQTL) dataset, comprising data from 31,684 individuals, was sourced from the eQTLGen consortium (J. Chen et al. 2024 ; Võsa et al. 2021 ). …