TenK10K multiome initiative : Genetic regulation of cell-type–specific chromatin accessibility shapes immune function and disease risk

Understanding how genetic variation influences gene regulation at the single-cell level is crucial for elucidating the mechanisms underlying complex diseases. However, limited large-scale single-cell multi-omics data have constrained our understanding of the regulatory pathways that link variants to gene expression. Here, we present the TenK10K multiome initiative as part of the TenK10K phase 1 projects: chromatin accessibility profiles from 3.5 million peripheral blood mononuclear cells (PBMCs) across 1,013 donors, generated using single-cell ATAC-seq and multiome (RNA+ATAC) sequencing, with matched whole-genome sequencing. We characterised ~441,000 chromatin peaks across 28 immune cell types and mapped ~243,000 chromatin accessibility QTLs (caQTLs), 60% of which are cell-type-specific. Integration with TenK10K scRNA-seq (5.4 million PBMCs) identified 31,688 candidate cis-regulatory elements colocalised with eQTLs; over half (52.5%) show evidence of causal effects mediated via chromatin accessibility. Combining caQTLs with GWAS loci for 17 diseases and 44 blood traits uncovered 10–41% more colocalised signals compared to eQTLs alone. For example, incorporating caQTLs increased the number of candidate inflammatory bowel disease (IBD) genes in CD8 effector memory T cells from 39 to 55. We demonstrate cell-type-specific mechanisms, such as a regulatory effect on IRGM acting through altered chromatin accessibility in CD8 effector memory T cells but not in naïve cells. Using a graphical neural network, we link peaks to genes in unpaired multiome data with up to 80% higher accuracy than with paired data lacking QTLs, improving gene regulatory network inference by identifying 128 additional TF–target pairs (a 22% increase). These findings provide an unprecedented single-cell map of chromatin accessibility and genetic variation in human circulating immune cells, establishing a powerful resource for dissecting cell-type-specific regulation and advancing our understanding of genetic risk for complex diseases.