Novel insight of critical genes involved in breast cancer brain metastasis: evidence from a cross-tissue transcriptome association study and validation through external clinical cohorts

BMC Cancer, Journal Year: 2025, Volume and Issue: 25(1)

Published: April 16, 2025

Breast cancer represents the most prevalent form of tumors among females and is characterized by a significant genetic component. The brain frequent site metastasis for breast cancer. Although numerous loci associated with (BCBM) have been identified, critical regulatory genes underlying BCBM remain largely unclear. FinnGen R11 dataset was combined Genotype-Tissue Expression Project (GTEx) Transcriptome-wide Association Study (TWAS). Unified Test Molecular Signatures (UTMOST), Multimarker Analysis Genomic Annotation (MAGMA), Functional Summary-based Imputation (FUSION) were used to identify candidate genes. Summary-data-based mendelian randomization (SMR) co-localization performed further elucidate association between key BCBM. Finally, multiple external cohorts obtained validate findings. In our study, 12 new identified TWAS. Subsequently, both SMR shown that CAPS8 only expressed in tissues including frontal cortex cerebellar hemispheres Potential regulation CASP8 could occur findings ultimately validated clinical cohorts. Our study gene CASP8, which BCBM, providing insights into occurrence

Language: Английский

A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 18, 2024

Abstract Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder with environmental factors being the primary risk determinants. However, genetic also substantially contribute to susceptibility and progression of COPD. Although genome-wide association studies (GWAS) have identified several loci associated COPD susceptibility, specific pathogenic genes underlying these loci, along their biological functions roles within regulatory networks, remain unclear. This lack clarity constrains our ability achieve deeper understanding basis study leveraged FinnGen R11 dataset, comprising 21,617 cases 372,627 controls, GTEx V8 eQTLs data conduct cross-tissue transcriptome-wide (TWAS). Initially, we performed TWAS analysis using Unified Test for Molecular Signatures (UTMOST), followed by validation UTMOST findings in single tissues Functional Summary-based Imputation (FUSION) method conditional joint (COJO) analyses genes. Subsequently, candidate were screened Multi-marker Analysis Genomic Annotation (MAGMA). The causal relationship between was further evaluated through summary data-based Mendelian randomization (SMR), colocalization analysis, (MR). Additionally, results validated against dataset GWAS Catalog (GCST90399694). GeneMANIA employed explore functional significance In 17 Among these, novel gene, G protein-coupled receptor kinase 4 (GRK4), single-tissue MAGMA analyses, confirmation via SMR, MR, analyses. Moreover, GRK4 an independent dataset. identifies as potential gene COPD, which may influence exacerbating inflammatory responses. address gaps previous studies, revealing consistent expression function across different tissues. considering study’s limitations, investigation ’s role are warranted.

Language: Английский

A Cross-Tissue Transcriptome-Wide Association Study Identifies WDPCP as a Potential Susceptibility Gene for Coronary Atherosclerosis

Atherosclerosis Plus, Journal Year: 2024, Volume and Issue: 58, P. 59 - 74

Published: Nov. 23, 2024

Coronary atherosclerosis (CAS) is a complex chronic inflammatory disease with significant genetic and environmental contributions. While genome-wide association studies (GWAS) have pinpointed many risk loci, over 75 % are in non-coding regions, complicating functional analysis understanding gene-disease mechanisms.

Language: Английский