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DTSTART;TZID=Australia/Sydney:20250811T130000
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SUMMARY:TenK10K multiome initiative: Genetic regulation of cell-type–specific chromatin accessibility shapes immune function and disease risk
DESCRIPTION:Statistical Bioinformatics SeminarDr Angli Xue\, Garvan Institute of Medical Research\n\n\n\nThis was an online event held via Zoom. \n\n\n\n\n\n\n\n\n\n\n\nUnderstanding 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. \n\n\n\n\n\n\nSubscribe to our seminar mailing list\n\n\n\n\n→\n\n\n\n\n\n\n\nFind out more about the Statistical Bioinformatics seminar series\n\n\n\n\n\n→\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nDr Angli Xue\n\n\n\nDr Angli Xue is an NHMRC Investigator Fellow (EL1) and a postdoctoral researcher with Prof Joseph Powell at the Garvan Institute of Medical Research. He currently leads the multiome stream of the TenK10K project — a population cohort study aiming to map 50 million human cells from 10\,000 individuals. His research focuses on leveraging large-scale multi-omics data to uncover cell type–specific genetic regulatory mechanisms and identify novel drug targets. Dr Xue earned his BSc from Zhejiang University and completed a PhD in Statistical Genetics at The University of Queensland under the supervision of Prof Jian Yang. He is the recipient of an NHMRC Investigator Grant (2025–2029) and a Ramaciotti Health Investment Grant as Chief Investigator.
URL:https://spds.sydney.edu.au/event/tenk10k-multiome-initiative-genetic-regulation-of-cell-type-specific-chromatin-accessibility-shapes-immune-function-and-disease-risk/
ATTACH;FMTTYPE=image/jpeg:https://spds.sydney.edu.au/wp-content/uploads/2025/02/Complex-systems-1-edited-scaled.jpeg
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