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Epigenetic Mediating Mechanisms in Parkinson's Disease: The Impact of Educational Attainment on SETD1A Expression.

BACKGROUND: This study investigated the interplay between environmental, genetic, and epigenetic factors in Parkinson's disease (PD) etiology, aiming to identify key factors and their impact on disease progression. METHODS: Leveraging genome-wide association study data of PD and environmental-related factors, in conjunction with blood expression quantitative trait loci (QTLs) and methylation QTLs data, we used two-sample Mendelian randomization (MR), summary data-based MR (SMR), and colocalization analysis to explore the association between environmental, epigenetic, and genetic factors and P…

Cell type-specific eQTL analysis of COVID-19 based on single-cell transcriptomic data.

Genome-wide association study analysis has revealed the significant influence of genetic factors in the progression of COVID-19. However, the impact of these genetic variants on gene expression in various cell types remains largely unexplored. Here, we profiled immune cells from 42 COVID-19 cases (involving five stages) and 11 healthy individuals, and performed a single-cell RNA-seq assay with >200 000 cells to investigate cell type-specific and stage-specific genetic effects of genetic variants. Single-cell expression quantitative trait loci analysis of eight distinct cell types showed that t…

Chelation-based iron uptake mitigates the effects of prolonged high-temperature stress in cool-season grasses.

High-temperature stress poses a significant threat to agricultural productivity and ecological diversity. Here, we show the effects of prolonged high-temperature stress on wheat (Triticum aestivum) and the model grass Brachypodium distachyon and demonstrate that heat stress induces iron deficiency in newly emerged leaves. Quantitative trait locus analysis of B. distachyon reveals a genomic region associated with heat resilience that includes the transporter of mugineic acid family phytosiderophores 1 gene (BdTOM1). Iron-deficiency-related genes including BdTOM1 are more highly expressed in a h

The methylation site cg06972019 regulates the succinylation-related gene ENO1 to inhibit the occurrence of erectile dysfunction.

BACKGROUND: This study aims to explore the causal relationship between the expression of succinylation-related genes and erectile dysfunction (ED). METHOD: Through a literature review, we identified 19 succinylation-related genes and intersected them with cis-expression Quantitative Trait Loci (cis-eQTL) data from the eQTLGen Consortium, ultimately selecting 16 genes with available cis-eQTL data. Subsequently, we downloaded genomic data related to erectile dysfunction (ED) from 223,805 European male participants in the IEU OpenGWAS project and performed a two-sample Mendelian Randomization (M…

IP-SNPs-seq links noncoding risk alleles to lineage transcription factor programs in prostate cancer.

Most prostate cancer risk variants reside in noncoding DNA, but connecting germline alleles to lineage transcription factor (TF) programs has been challenging. We developed immunoprecipitation-coupled SNPs-seq (IP-SNPs-seq), enabling high-throughput, allele-specific, TF-resolved interrogation of candidate regulatory variants. Screening 903 prostate cancer-associated SNPs with androgen receptor (AR) immunoprecipitation, we identified multiple alleles with biased AR binding and convergent evidence from eQTL and ChIP-seq datasets. Among these, rs7600820 emerged as a functional enhancer variant: t

Integrating single-cell RNA sequencing and Mendelian randomization analysis to identify potential drug targets for dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM), a leading cause of heart failure and sudden cardiac death, lacks therapies targeting disease progression. Genome-wide association studies (GWAS) have identified genetic loci linked to DCM, but translating these findings into actionable drug targets remains challenging. Integrating the druggable genome with multi-omics approaches offers a promising strategy for precision therapy. METHODS: We combined Mendelian randomization (MR), Bayesian co-localization, and single-cell RNA sequencing to identify causal drug targets for DCM. Tissue-specific cis-eQTL an

Hair follicle gene expression profiling in the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS).

BACKGROUND: Transcriptomic analysis is common in large cohort studies but is generally restricted to cells in blood, which limits inferences about organs of interest, and direct organ sampling is mostly infeasible in large cohorts. New techniques for RNA-seq from noninvasive biosamples may provide the opportunity to profile transcriptomes of additional tissues for more organ-relevant insights at scale. We investigated the feasibility and utility of hair follicle gene expression profiling in a multi-center study of chronic obstructive pulmonary disease (COPD). METHODS: Bulk RNA-seq was perform

Multiomics integration prioritizes potential drug targets for multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disease with no current cure. Drug discovery and repurposing are essential to enhance treatment efficacy and safety. We utilized summary statistics for protein quantitative trait loci (pQTL) of 2,004 plasma and 1,443 brain proteins, a genome-wide association study of MS susceptibility with 14,802 cases and 26,703 controls, both bulk and cell-type specific transcriptome data, and external pQTL data in blood and brain. Our integrative analysis included a proteome-wide association study to identify MS-associated proteins, followed by summary-data-base…

Многоомичные биомаркеры, связанные с множественным склерозом: от менделианской случайности до прогнозирования наркотиков.

В настоящее время лечение и профилактика множественных склерозов (МС) по-прежнему сталкиваются с серьезными проблемами. Одним из важнейших методов проведения исследований в рамках реализации новых терапевтических стратегий стал менделийский анализ случайности (МСР). Соответственно, мы предполагаем, что существует причинно-следственная связь между генетическими вариантами конкретных плазменных белков и MS с помощью механизмов MR и что ключевые терапевтические цели можно точно определить путем интеграции многомерных аналитических подходов. В этом исследовании мы разработали всеобъемлющую аналити

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… Employing a recursive conditional analysis approach, the precomputed summary statistics highlight the most significant variant within each region (± 1 Mb) as a sentinel plasma pQTL ( n  = 18,084), while other variants are categorized as minor plasma protein quantitative trait loci ( n  = 10,107). … Thirdly, the expression quantitative trait loci (eQTLs) vary with disease progression due to differences in cell types. The eQTLs derived from bulk RNA sequencing face significant constraints when elucidating the key molecular mechanisms associated with diseases. …

Multi-omics analysis reveals the genetic aging landscape of Parkinson's disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer's disease. Despite numerous studies, specific age-related factors remain unidentified. This study employed a multi-omics approach to investigate the link between PD and aging. We integrated blood gene expression profiles, expression quantitative trait loci, genome-wide association studies, predictive models, and conducted clinical validation.By analyzing PD datasets, a total of 953 differentially expressed genes (DEGs) and 10 intersecting aging differentially expressed genes (ADEGs) were id…

Genetic and transcriptomic landscape of colonic diverticulosis.

OBJECTIVE: Colonic diverticulosis is a prevalent condition among older adults, marked by the presence of thin-walled pockets in the colon wa … variation with single-cell RNA-seq data from the human intestine. We also integrated our expression quantitative trait loci with genome-wide association study using Mendelian randomisation (MR). Furthermore, a Polygenic Risk Score analysis gauged associations between diverticulosis severity and other gastrointestinal disorders. RESULTS: We discerned 38 genes with differ …

Investigating potential novel therapeutic targets and biomarkers for ankylosing spondylitis using plasma protein screening.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and sacroiliac joints. Recent genetic studies suggest certain plasma proteins may play a causal role in AS development. This study aims to identify and characterize these proteins using Mendelian randomization (MR) and colocalization analyses. METHODS: Plasma protein data were obtained from recent publications in Nature Genetics, integrating data from five previous GWAS datasets, including 738 cis-pQTLs for 734 plasma proteins. GWAS summary data for AS were sourced from IGAS and other European cohort

Genome wide association study and meta-analysis identified multiple new risk loci for freckles in 4813 Chinese individuals.

Freckle is a prevalent pigmentary dermatosis with an obvious hereditary component. Dozens of freckles risk loci have been discovered through research on multiple traits or other diseases, rather than as an independent trait. To discover novel variants associated with freckles, we performed GWAS and meta-analysis in 4813 Chinese individuals. We conducted GWAS and meta-analysis of two cohorts: 197 patients and 1603 controls (Cohort I), and 336 patients and 2677 controls (Cohort II), both from China. Then we performed linkage disequilibrium (LD) analysis, eQTL study, and enrichment analysis with

Joint models reveal genetic architecture of pubertal stage transitions and their association with BMI in admixed Chilean population.

Early or late pubertal onset can lead to disease in adulthood, including cancer, obesity, type 2 diabetes, metabolic disorders, bone fractur … which causes ovarian dysfunction when mutated. The associated variants are expression and splicing Quantitative Trait Loci regulating gene expression and alternative splicing in multiple tissues. Further, higher individual Native American genetic ancestry proportions predicted a significantly earlier puberty onset in boys but not in girls. Finally, the joint models iden …

Genetic basis and identification of candidate genes for wooden breast and white striping in commercial broiler chickens.

Wooden breast (WB) and white striping (WS) are highly prevalent and economically damaging muscle disorders of modern commercial broiler chic … estimated at 0.5 for WB and WS with high genetic correlation between them (0.88). GWAS revealed 28 quantitative trait loci (QTL) on five chromosomes for WB and 6 QTL on one chromosome for WS, with the majority of QTL for both myopathies located in a ~ 8 Mb region of chromosome 5. This region has highly conserved synteny with a portion of human chromosome 11 containing a …

Self-reported hearing loss questions provide a good measure for genetic studies: a polygenic risk score analysis from UK Biobank.

Age-related hearing impairment (ARHI) is very common in older adults and has major impact on quality of life. The heritability of ARHI has been estimated to be around 50%. The present study aimed to estimate heritability and environmental contributions to liability of ARHI and the extent to which a polygenic risk score (PRS) derived from a recent genome-wide association study of questionnaire items regarding hearing loss using the UK Biobank is predictive of hearing loss in other samples. We examined (1) a sample from TwinsUK who have had hearing ability measured by pure-tone audiogram and the

miRNA Expression and Interaction with Genes Involved in Susceptibility to Pristane-Induced Arthritis.

Pristane-induced arthritis (PIA) in mice is an experimental model that resembles human rheumatoid arthritis, a chronic autoimmune disease that affects joints and is characterized by synovial inflammation and articular cartilage and bone destruction. AIRmax and AIRmin mouse lines differ in their susceptibility to PIA, and linkage analysis in this model mapped arthritis severity QTLs in chromosomes 5 and 8. miRNAs are a class of small RNA molecules that have been extensively studied in the development of arthritis. We analyzed miRNA and gene expression profiles in peritoneal cells of AIRmax and

Genomic regulation of type 2 diabetes endophenotypes: Contribution from genetic studies in the Goto-Kakizaki rat.

The inbred Goto-Kakizaki (GK) rat strain is a unique model of spontaneous type 2 diabetes mellitus caused by naturally occurring genetic variants that have been selectively isolated from an outbred colony of Wistar rats. Genetic and genomic studies in experimental crosses and congenic strains of the GK have shed light on the complex etiopathogenesis of diabetes phenotypes in this model. Diabetes-related phenotypes in the GK are under polygenic control and distinct genetic loci regulate glucose tolerance, insulin secretion, β-cell mass and plasma lipids. Metabolome and transcriptome profiling d

X-inactivation informs variance-based testing for X-linked association of a quantitative trait.

BACKGROUND: The X chromosome plays an important role in human diseases and traits. However, few X-linked associations have been reported in genome-wide association studies, partly due to analytical complications and low statistical power. RESULTS: In this study, we propose tests of X-linked association that capitalize on variance heterogeneity caused by various factors, predominantly the process of X-inactivation. In the presence of X-inactivation, the expression of one copy of the chromosome is randomly silenced. Due to the consequent elevated randomness of expressed variants, females that a

Natural bone fragmentation in the blind cave-dwelling fish, Astyanax mexicanus: candidate gene identification through integrative comparative genomics.

Animals that colonize dark and nutrient-poor subterranean environments evolve numerous extreme phenotypes. These include dramatic changes to the craniofacial complex, many of which are under genetic control. These phenotypes can demonstrate asymmetric genetic signals wherein a QTL is detected on one side of the face but not the other. The causative gene(s) underlying QTL are difficult to identify with limited genomic resources. We approached this task by searching for candidate genes mediating fragmentation of the third suborbital bone (SO3) directly inferior to the orbit of the eye. We integr