Single-Cell Multi-Omics Insights into BMI-Mediated Immune-Related Disease Risk

Abstract This study is based on the Chinese Immune Multi-Omics Atlas (CIMA) cohort and performs an integrated single-cell multi-omics analysis of peripheral blood mononuclear cells (PBMCs) from 210 individuals aged 20-29, comprising 3,311,699 scRNA-seq cells and 1,839,860 scATAC-seq cells, to decipher immune characteristics across different body mass index (BMI) categories. By integrating gene regulatory network (GRN) and cell type-level molecular quantitative trait loci (xQTL) data, and conducting summary-data-based Mendelian randomization (SMR) analysis in conjunction with genome-wide association studies (GWAS) of BMI-mediated immune-related diseases, we identified key disease-associated cell types and molecular features. Using rheumatoid arthritis (RA) as an example, multi-omics evidence revealed that in MAIT-SLC4A10 cells of underweight individuals, increased chromatin accessibility at the CCR6 locus (chr6:167119627-167120128) and enhanced transcriptional activity of RORC/RORA collectively drive elevated CCR6 expression, which may represent a potential molecular mechanism underlying the higher risk of RA in underweight populations. Our study leverages single-cell multi-omics data to systematically dissect the molecular mechanisms by which different BMI categories mediate susceptibility to immune-related diseases through coordinated regulation of immune cell chromatin accessibility, transcription factor activity, and downstream gene expression.