Publication Date
9-12-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-52356-9
PMID
39266564
PMCID
PMC11392933
PubMedCentral® Posted Date
9-12-2024
PubMedCentral® Full Text Version
Post-Print
Published Open-Access
yes
Keywords
Humans, Lung Neoplasms, Genetic Predisposition to Disease, Genome-Wide Association Study, Single-Cell Analysis, Transcriptome, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Chromatin, Male, Female, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, Multiomics, Lung cancer, Gene expression profiling, Epigenomics, Risk factors, Cancer epidemiology
Abstract
Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function.
Included in
Diseases Commons, Epidemiology Commons, Medical Sciences Commons, Oncology Commons, Pulmonology Commons
Comments
This article has been corrected. See Nat Commun. 2024 Nov 18;15:9969.
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