Single-cell multiomic profiling of lung immune cells identifies novel asthma risk genes and cell-type specific functions

Genetic variants associated with asthma are mostly in non-coding regions, so it is challenging to identify their target genes and the cellular contexts. Functional profiling of blood immune cell types has helped link asthma risk variants to functions. However, lung immune cells differ from those circulating in blood, and high-resolution functional genomic data of lung immune cells are lacking. Here we profiled single-cell multi-omics (RNA-seq and ATAC-seq) on lymphocytes of lung and spleen tissues. Cross-tissue comparison identified distinct transcriptomes for each immune cell type, but subtle differences in chromatin accessibility. We then assessed open chromatin regions of lung vs. blood, using a public dataset, for their enrichment of asthma risk. Strikingly, lung T cells show unique contributions to heritability of adult-onset (AOA) and childhood-onset asthma (COA), beyond blood T cells. We further identified 43 cis-regulatory elements (CREs) likely contributing to asthma risk. With enhancer-gene maps built from our single-cell data, we identified target genes for these CREs, including CCR4 and LRRC32 that show cell-type specific regulatory activities. These findings demonstrate the utility of single-cell multiomics to identify asthma risk genes and understand their cell-type specific functions.