Tu166 - Deciphering State-dependent Immune Features at Single-cell Resolution from Multi-layer Human Omics Including Transcriptomics, Germline Variants, Mosaic Chromosomal Alterations, and Plasma Proteomics

Abstract Text: Multi-omics molecular quantitative trait locus (mQTL) analyses elucidate biological mechanisms of human diseases, while current mQTL catalogues are mostly at bulk resolution and centered on Europeans. Here, we constructed immune single-cell atlas with multi-layer omics from 235 Japanese, including COVID-19 patients and healthy subjects. Dataset consists of single-cell transcriptomics from >1.5 million peripheral blood mononuclear cells, host genetics, plasma proteomics, and gut metagenomics. We mapped the germline genetic effects on gene expression within immune cell types and across cell states. We elucidated cell type and context-specific HLA and genome-wide associations with T/B cell receptor repertoires (e.g., COVID-19 and HLA class I interactions in CD8+ T cells). Colocalization utilizing dynamic genetic regulation of gene expression provided better understandings of genome-wide association signals. Differential gene and protein expression analysis depicted cell type and context-specific effects of polygenic risks. Leveraging whole-genome sequencing and SNP genotyping, we projected various somatic mutations such as mosaic chromosomal alterations (mCAs), loss of Y chromosome (LOY), and mitochondrial DNA heteroplasmy into single-cell resolution, which were highly cell type-specific. We identified immune features specific to somatically mutated cells (e.g., monocyte-specific accumulation of LOY). In-vitro analysis of clonally expanded mCAs in a COVID-19 patient using single-cell B cell receptor showed no reactivity against SARS-CoV-2 antigens. Single-cell technology resolved associations between disease-related gut bacteria and peripheral immune cells abundance. Thus, immune cells were dynamically regulated in a cell state-dependent manner characterized with multi-omics profiles. Our study shows a value of multi-omics anchored by single-cells to interpret biological phenomena at fine resolution.