Allelic imbalance of chromatin accessibility in cancer identifies candidate causal risk variants and their mechanisms.

ABSTRACT: While many germline cancer risk variants have been identified through genome-wide association studies (GWAS), the mechanisms by which these variants operate remain largely unknown. Here we used 406 cancer ATAC-Seq samples across 23 cancer types to identify 7,262 germline allele-specific accessibility QTLs (as-aQTLs). Cancer as-aQTLs had stronger enrichment for cancer risk heritability (up to 145 fold) than any other functional annotation across seven cancer GWAS. Most cancer as-aQTLs directly altered transcription factor (TF) motifs and exhibited differential TF binding and gene expression in functional screens. To connect as-aQTLs to putative risk mechanisms, we introduced the regulome-wide associations study (RWAS). RWAS identified genetically associated accessible peaks at >70% of known

SUBMITTER: Grishin D 

PROVIDER: S-EPMC9886437 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature