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Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes
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Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes
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Journal Article
Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes
2024
Overview
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.
Multiple genetic loci are associated with lung cancer risk, but the underlying genetic mechanisms remain poorly understood. Here, the authors perform single-cell RNA-seq and ATAC-seq analyses of lung cells from ever- and never-smokers; they report candidate cis-regulatory elements that colocalise with candidate causal variants in lung cancer risk loci and potential susceptibility genes.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 692/499
/ Context
/ Female
/ Gene Expression Regulation, Neoplastic
/ Genes
/ Genetic Predisposition to Disease
/ Genome-wide association studies
/ Genome-Wide Association Study
/ Humanities and Social Sciences
/ Humans
/ Male
/ Polymorphism, Single Nucleotide
/ Regulatory Sequences, Nucleic Acid - genetics
/ Risk
/ Science
/ Single-Cell Analysis - methods
/ Smoking
