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Nat Genet DOI:10.1038/s41588-022-01075-2

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

Publication TypeJournal Article
Year of Publication2022
AuthorsGrishin, D, Gusev, A
JournalNat Genet
Volume54
Issue6
Pages837-849
Date Published2022 Jun
ISSN1546-1718
KeywordsAllelic Imbalance, Chromatin, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Neoplasms, Polymorphism, Single Nucleotide
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 breast and prostate loci and discovered new risk loci in all examined cancer types. Integrating as-aQTL discovery, motif analysis and RWAS identified candidate causal regulatory elements and their probable upstream regulators. Our work establishes cancer as-aQTLs and RWAS analysis as powerful tools to study the genetic architecture of cancer risk.

DOI10.1038/s41588-022-01075-2
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35697866?dopt=Abstract

Alternate JournalNat Genet
PubMed ID35697866
Grant ListR01 MH115676 / MH / NIMH NIH HHS / United States
R01 CA227237 / CA / NCI NIH HHS / United States
R01 CA244569 / CA / NCI NIH HHS / United States
R01 CA259200 / CA / NCI NIH HHS / United States
R01 MH115676 / MH / NIMH NIH HHS / United States
R01 CA227237 / CA / NCI NIH HHS / United States
R01 CA244569 / CA / NCI NIH HHS / United States
R01 CA259200 / CA / NCI NIH HHS / United States