Systematic Identification and Characterization of Causal Risk Genes Implicated in Colorectal Cancer by Integrating...

Area of Science:

• Genomics
• Cancer Biology
• Bioinformatics

Background:

• Single-nucleotide polymorphisms (SNPs) influence colorectal cancer (CRC) susceptibility, but their functional mechanisms remain unclear.
• Genome-wide association studies (GWAS) identify noncoding SNPs, yet their roles in gene expression, DNA methylation, and gut microbiota interactions require characterization.
• Understanding these mechanisms is crucial for identifying biomarkers for early CRC diagnosis and intervention.

Purpose of the Study:

• To develop an integrative framework for prioritizing causal risk genes at CRC-associated GWAS loci.
• To explore the functional effects of genetic variations on gene expression, DNA methylation, and gut microbiome.
• To identify potential biomarkers for CRC diagnosis and therapeutic strategies.

Main Methods:

• Utilized an integrative framework employing Summary-data-based Mendelian randomization and heterogeneity in dependent instruments (SMR&HEIDI) and Two-sample Mendelian Randomisation (TSMR) methods.
• Validated findings through gene expression analysis and transcription factor (TF) binding affinity assessments.
• Integrated multi-omics data including GWAS, gene expression, DNA methylation, and gut microbiome data.

Main Results:

• Identified 10 tissue-specific gene-SNP pairs, 3 blood eQTL-gene pairs, 26 gene-CpG-SNP regulatory modules, and 39 microbiota-associated gene-SNP pairs.
• Discovered potential regulatory influences on CRC development, including POU5F1B and rs10797801.
• Observed that genetic variants disrupted TF binding affinity, with few promoting TF binding.

Conclusions:

• Data integration successfully prioritized genes based on regulatory mechanisms like gene expression and DNA methylation.
• Multi-omics integration identified causal risk genes and variants associated with CRC susceptibility.
• Findings provide insights into CRC molecular mechanisms and potential avenues for diagnosis and therapeutic interventions.