Lightning Talk GENEMAPPERS 2026

TenK10K multiome project: Genetic regulation of cell type–specific chromatin accessibility shapes immune function and disease risk (#14)

Angli Xue 1 2 , Jayden Fan 1 2 , Oscar A Dong 1 3 , Hao Huang 1 2 4 , Peter C Allen 1 2 , Eleanor Spenceley 1 2 , Eszter Sagi-Zsigmond 1 , Blake Bowen 1 2 , Anna SE Cuomo 1 2 4 5 6 , Albert Henry 1 2 , Hope A Tanudisastro 2 5 6 7 , Zhen Qiao 2 8 , Ling Chen 9 , Eyal Ben-David 9 , Kyle Kai-How Farh 9 , Drew Neavin 1 , Arthur S Lee 10 11 , Anne Senabouth 1 , Caitlin Bartie 1 , Rachael A Zekanovic 1 , Venessa Chin 1 2 12 , Katrina M de Lange 5 6 , Gemma A Figtree 13 14 , Alex W Hewitt 15 16 17 , Daniel MacArthur 2 5 6 , Joseph E Powell 1 2 4
  1. Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
  3. Faculty of Science, University of Sydney, Sydney, NSW, Australia
  4. UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, NSW, Australia
  5. Centre for Population Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia
  6. Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, VIC, Australia
  7. Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  8. Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
  9. Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
  10. Massachusetts General Hospital, Boston, MA, USA
  11. The Broad Institute of MIT and Harvard, Cambridge, MA, USA
  12. The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia
  13. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
  14. Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia
  15. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
  16. Department of Ophthalmology, Royal Hobart Hospital, Hobart, TAS, Australia
  17. Centre for Eye Research Australia, University of Melbourne, East Melbourne, VIC, Australia

Understanding how genetic variation influences gene regulation at 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 cell-type-specific gene expression. Here we present chromatin accessibility profiles from 3.5 million peripheral blood mononuclear cells (PBMCs) across 1,042 donors, generated using single-cell ATAC-seq and multiome (RNA+ATAC) sequencing, with matched whole-genome sequencing, generated as part of the TenK10K program. We characterised 440,996 chromatin peaks across 28 immune cell types and mapped 243,273 chromatin accessibility quantitative trait loci (caQTLs), 60% of which are cell-type-specific. We then did fine-mapping and detected 20,834 caQTLs with >1 credible set that contains causal variants. Integration with TenK10K scRNA-seq data (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. Integrating caQTLs with GWAS summary statistics for 16 diseases and 44 blood traits uncovered 9.8% - 30.0% more colocalized signals compared with using eQTLs alone, many of which are due to multiple underlying causal variants. We demonstrate cell-type-specific mechanisms, such as a regulatory effect on IRGM acting through altered promoter chromatin accessibility in CD8 effector memory T cells but not in naïve cells. Using a graph-linked embedding approach, we inferred peak-to-gene relationships from unpaired multiome data by incorporating caQTL and eQTL signals, achieving up to 80% higher accuracy compared to using paired multiome data without QTL information. This improvement further enhanced gene regulatory network inference, leading to the identification of 128 additional transcription factor (TF)–target gene 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.

  1. Xue et al. medRxiv. 2025. https://doi.org/10.1101/2025.08.27.25334533