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IBAS: Interaction-bridged association studies discovering novel genes underlying complex traits.

Genetic contributions to complex traits are often mediated through coordinated gene-gene interaction networks, yet most existing association frameworks focus on marginal single-gene effects and overlook higher-order dependency structures. Direct modeling of interactions remains challenging due to combinatorial complexity and statistical instability. We introduce Interaction-Bridged Association Study (IBAS), a general framework that incorporates pathway-level interaction patterns into genotype-phenotype association analysis without explicitly enumerating interactions. IBAS leverages transcripto

Comparative GWAS using global and Indian Reference Panels reveals non-coding drivers of COVID-19 severity and mortality.

India remains underrepresented in global genomic studies. We hypothesized that population-specific genetic variants contribute to COVID-19 severity and outcomes, and that the choice of reference panel during imputation impacts Genome-Wide Association Studies (GWAS) resolution. Integrating both global and indigenous reference panels may unravel unique and shared genetic associations that are otherwise missed during standard analyses. In this study, we aimed to perform a comparative GWAS using Indian population-specific (IndiGen) and global (1000 Genomes Project/1KGenomes) reference panels to id

Exploring Genetic Contributions to Prostate Cancer Risk in an Asian Population-Based Study.

BACKGROUND: Genetic susceptibility to prostate cancer (PCa) varies across populations, yet East Asian men remain underrepresented in genome- … enoMic Annotation (MAGMA), functional annotation using HaploReg, and prostate tissue cis-expression quantitative trait loci (cis-eQTL) and splicing QTL (sQTL) evaluation using the Genotype-Tissue Expression project (GTEx) were performed to explore functional relevance. RESULTS: We identified 371 genome-wide significant variants and 47 independent risk loci, including es …

Transcriptome analysis in osteoarthritis primary tissues identifies high-confidence effector genes.

Osteoarthritis, a whole-joint degenerative disorder, is a major public health burden that affects nearly 600 million individuals worldwide, … n = 212) cartilage, synovium (n = 277), and fat pad (n = 92). We identify 10,166 unique expression quantitative trait loci (eQTL)-associated genes, 61.1% of which have not been reported in previous osteoarthritis eQTL studies, and uncover cartilage grade-specific genetic regulation. Using the largest osteoarthritis genome-wide association study to date, we find colocali …

Integrative genomic characterization of the FADS1-2-3 mood disorder risk locus: implications for the role of polyunsaturated fatty acids.

BACKGROUND: Polyunsaturated fatty acids (PUFA) have been implicated in mood disorder pathophysiology, with Mendelian randomisation studies suggesting a causal role. However, much of this evidence centres on the highly pleiotropic FADS1-2-3 gene cluster, raising concerns about horizontal pleiotropy and uncertainty regarding the true effector gene(s). To assess the validity of these concerns, we performed integrative genetic characterization of the FADS1-2-3 mood disorder risk locus. METHODS: We analysed summary statistics from the largest (up to n = 4 million) genome-wide association studies (

Mapping the immune-genetic architecture of Epstein-Barr virus-related phenotypes and multiple sclerosis through a single-cell genetic framework for target prioritization and pharmacologic hypothesis generation.

BACKGROUND: Multiple sclerosis (MS) is a severe neuroinflammatory disease causing substantial long-term disability. Strong epidemiologic evidence links Epstein-Barr virus (EBV) exposure with MS risk, but genetic evidence for immune target prioritization in EBV-related phenotypes remains limited. METHODS: We integrated single-cell cis-eQTL data from 14 immune cell types with GWASs of an EBV-related clinical phenotype and MS using a single-cell Mendelian randomization framework with colocalization analyses. Candidate eGenes were evaluated in independent cohorts. For multi-SNP instruments, we pe

Alzheimer's disease multi-ancestry genome-wide interaction and stratified study with smoking.

INTRODUCTION: Alzheimer's disease (AD) has genetic and environmental risk factors, including cigarette smoking. Gene-environment interactions may explain AD missing heritability. METHODS: Lifetime smoking data from 22,032 European ancestry and 3126 African ancestry participants from the Alzheimer's Disease Genetic Consortium and the Framingham Heart Study were used to conduct genome-wide single nucleotide polymorphism (SNP)-by-smoking interaction and smoking-stratified association studies. For top-ranked loci, brain-derived bulk and single nuclei RNA-sequencing were used for differential expr

Single-cell eQTL analysis identifies genetic variation underlying metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized for its medical and socioeconomic impacts, driven by diverse genetic and environmental factors. Here, to address the urgent need for individually tailored therapies, we show results from single-cell expression quantitative trait locus (sc-eQTL) analysis on liver biopsies from 25 patients with MASLD and 23 controls. This approach identified over 3,500 sc-eQTLs across major liver cell types and cell-state-interacting eQTLs (ieQTLs) with significant enrichment for disease heritability (for MASLD trait, ieQ

A genome-wide association study of European advanced cancer patients treated with opioids identifies regulatory variants on chromosome 20 associated with pain intensity.

BACKGROUND: Opioids in step III of the WHO analgesic ladder are the standard of care for treating cancer pain. However, a significant minori … nociceptin receptor 1. Notably according to the eQTLGen database, these variants act as expression quantitative trait loci, modulating the expression mainly of PCMTD2 but also of OPRL1. Variants in the same chromosomal region were recently reported to be significantly associated with pain intensity in a GWAS conducted in subjects with different chronic pain conditions. …

Genetic Analysis of the X Chromosome Associates Loci with Progression of Parkinson's Disease.

BACKGROUND: Genetic variants on the X chromosome have been linked to susceptibility for Parkinson's disease (PD), but their roles in disease progression remain unclear. OBJECTIVES: This study investigated associations between X chromosome variants and longitudinal cognitive decline or motor impairment in patients with PD. METHODS: We conducted combined (male + female) and stratified X-chromosome-wide survival studies (XWSS) in 4467 patients with PD with 33,406 longitudinal visits. Cognitive decline was defined as global cognitive impairment (GCI, Mini Mental State Exam score ≤25), whereas mo

The Functional Impact of the Noncoding SNP rs3741442 on Orofacial Clefting.

Orofacial cleft (OFC) is a common congenital anomaly in humans with variable birth prevalence in different ethnic groups. Although genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with nonsyndromic OFC (nsOFC), understanding of the underlying biological mechanisms of causative SNPs and genes in nsOFC remains limited. Here, we report that the noncoding SNP, rs3741442, has an expression quantitative trait locus (eQTL) effect on epithelial genes associated with periderm differentiation. Using a combination of epigenetic markers and in silico

Изучение связи между 91 циркуляцией воспламенительных протеинов и нейродегенеративными заболеваниями: двухнаправленный анализ менделей и биоинформатики.

Циркуляция подстрекательских белков играет важную роль в патогенезе нейродегенеративных заболеваний (НДД). Однако точная причинно-следственная связь и механизмы, лежащие в основе их взаимодействия, по-прежнему остаются неясными. МЕТОДЫ: В каталоге GWAS были получены данные по 91 циркуляционному подстрекательскому протеину в рамках исследования ассоциации геномов (GWAS). Кроме того, данные GWAS о болезни Паркинсона (PD), болезни Альцгеймера (AD), амиотропическом боковом склерозе (ALS), множественном склерозе (MS) и ишемическом инсульте (IS) были получены в рамках проекта IEU Open GWAS. Для анал

Совпадение в аннотации оригинала
BACKGROUND: Circulating inflammatory proteins play a significant role in the pathogenesis of neurodegenerative diseases (NDDs). However, the … employed to analyze causal effects, accompanied by sensitivity and pleiotropy analyses. Expression quantitative trait loci (eQTL) analyses for CD40 and MS-associated SNPs were performed. Transcriptomic data from the peripheral blood of MS patients were used to identify differentially expressed genes (DEGs) in relapsing-remitting MS (RRMS). RRMS patients were divided int …

Association of circulating cytokine levels and tissue-infiltrating myeloid cells with achalasia: results from Mendelian randomization and validation through clinical characteristics and single-cell RNA sequencing.

BACKGROUND: Achalasia is a rare motility disorder of the esophagus often accompanied by immune dysregulation, yet specific underlying mechanisms remain poorly understood. METHODS: We utilized Mendelian randomization (MR) to explore the causal effects of cytokine levels on achalasia, with cis-expression/protein quantitative trait loci (cis-eQTLs/pQTLs) for 47 cytokines selected from a genome-wide association study (GWAS) meta-analysis and GWAS data for achalasia obtained from FinnGen. For cytokines significantly linked to achalasia, we analyzed their plasma concentrations and expression differ…

Polygenic TB control and the sequence of innate/adaptive immune responses to infection: MHC-II alleles determine the size of the S100A8/9-producing neutrophil population.

Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2-congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC-II) region from TB-susceptible H2j mice transferred onto the genetic background of the TB-resistant C57BL/6 (H2b) strain. Susceptible B6.I-9.3 mice differ from B6 prog…

A multi-ancestry cerebral cortex transcriptome-wide association study identifies genes associated with smoking behaviors.

Transcriptome-wide association studies (TWAS) have provided valuable insight in identifying genes that may impact cigarette smoking. Most of previous studies, however, mainly focused on European ancestry. Limited TWAS studies have been conducted across multiple ancestries to explore genes that may impact smoking behaviors. In this study, we used cis-eQTL data of cerebral cortex from multiple ancestries in MetaBrain, including European, East Asian, and African samples, as reference panels to perform multi-ancestry TWAS analyses on ancestry-matched GWASs of four smoking behaviors including smoki

Proteome-wide Mendelian randomization and functional studies uncover therapeutic targets for polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is an endocrine syndrome that affects a large portion of women worldwide. This proteogenomic and functional study aimed to uncover candidate therapeutic targets for PCOS. We comprehensively investigated the causal association between circulating proteins and PCOS using two-sample Mendelian randomization analysis. Cis-protein quantitative trait loci were derived from six genome-wide association studies (GWASs) on plasma proteome. Genetic associations with PCOS were obtained from a large-scale GWAS meta-analysis, FinnGen cohort, and UK Biobank. Colocalization a…

Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility.

Among multiple sclerosis (MS) susceptibility genes, the strongest non-human leukocyte antigen (HLA) signal in the Italian population maps to the TNFSF14 gene encoding LIGHT, a glycoprotein involved in dendritic cell (DC) maturation. Through fine-mapping in a large Italian dataset (4,198 patients with MS and 3,903 controls), we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region. Expression quantitative trait locus (eQTL) analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells,

Hepatocellular carcinoma risk variant modulates lncRNA HLA-DQB1-AS1 expression via a long-range enhancer-promoter interaction.

Substantial evidence highlighted the critical role of long non-coding RNAs (lncRNA) in driving hepatocarcinogenesis. We hypothesized that functional variants in genome-wide association studies (GWASs) associated loci might alter the expression levels of lncRNAs and contribute to the development of hepatocellular carcinoma (HCC). Here, we prioritized potentially cis-expression quantitative trait loci-based single nucleotide polymorphism (SNP)-lncRNA association together with the physical interaction by the analyses from Hi-C data in GWAS loci of chronic hepatitis B and HCC. Subsequently, by lev…

Genome-wide association study to identify genomic regions and positional candidate genes associated with male fertility in beef cattle.

Fertility plays a key role in the success of calf production, but there is evidence that reproductive efficiency in beef cattle has decreased during the past half-century worldwide. Therefore, identifying animals with superior fertility could significantly impact cow-calf production efficiency. The objective of this research was to identify candidate regions affecting bull fertility in beef cattle and positional candidate genes annotated within these regions. A GWAS using a weighted single-step genomic BLUP approach was performed on 265 crossbred beef bulls to identify markers associated with

Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs271470