Systematic analysis of the effects of genetic variants on chromatin accessibility to decipher functional variants in non-coding regions

Genome-wide association study (GWAS) has identified thousands of single nucleotide polymorphisms (SNPs) associated with complex diseases and traits. However, deciphering the functions of these SNPs still faces challenges. Recent studies have shown that SNPs could alter chromatin accessibility and result in differences in tumor susceptibility between individuals. Therefore, systematically analyzing the effects of SNPs on chromatin accessibility could help decipher the functions of SNPs, especially those in non-coding regions. Using data from The Cancer Genome Atlas (TCGA), chromatin accessibility quantitative trait locus (caQTL) analysis was conducted to estimate the associations between genetic variants and chromatin accessibility. We analyzed caQTLs in 23 human cancer types and identified 9,478 caQTLs in breast carcinoma (BRCA). In BRCA, these caQTLs tend to alter the binding affinity of transcription factors, and open chromatin regions regulated by these caQTLs are enriched in regulatory elements. By integrating with eQTL data, we identified 141 caQTLs showing a strong signal for colocalization with eQTLs. We also identified 173 caQTLs in genome-wide association studies (GWAS) loci and inferred several possible target genes of these caQTLs. By performing survival analysis, we found that similar to 10% caQTLs potentially influence the prognosis of patients. To facilitate access to relevant data, we developed a user-friendly data portal, BCaQTL (http://gong_lab.hzau.edu.cn/caqtl_database), for data searching and downloading. Our work may facilitate fine-map regulatory mechanisms underlying risk loci of cancer and discover the biomarkers or therapeutic targets for cancer prognosis. The BCaQTL database will be an important resource for genetic and epigenetic studies.

Automated summary

Genome-wide association studies have identified thousands of SNPs associated with complex diseases and traits, but deciphering their functions remains challenging. Recent studies have shown that SNPs can alter chromatin accessibility, leading to differences in tumor susceptibility between individuals. Using caQTL analysis, we identified 9478 caQTLs in breast carcinoma that tend to alter transcription factor binding affinity and regulate open chromatin regions enriched in regulatory elements. Integration with eQTL data allowed us to identify caQTLs showing strong signals for colocalization with eQTLs, as well as caQTLs in GWAS loci. Survival analysis revealed that around 10% of caQTLs potentially influence patient prognosis. A user-friendly data portal, BCaQTL, was developed to provide easy access to relevant data. Our work facilitates the fine-mapping of regulatory mechanisms underlying cancer risk loci and the discovery of biomarkers or therapeutic targets for cancer prognosis.