Mapping genetic effects on cell type-specific chromatin accessibility and annotating complex trait variants using single nucleus ATAC-seq
Benaglio, P.; Newsome, J.; Han, J. Y.; Chiou, J.; Aylward, A.; Corban, S.; Okino, M.-L.; Kaur, J.; Gorkin, D.; Gaulton, K. J.
Show abstract
Gene regulation is highly cell type-specific and understanding the function of non-coding genetic variants associated with complex traits requires molecular phenotyping at cell type resolution. In this study we performed single nucleus ATAC-seq (snATAC-seq) and genotyping in peripheral blood mononuclear cells from 10 individuals. Clustering chromatin accessibility profiles of 66,843 total nuclei identified 14 immune cell types and sub-types. We mapped chromatin accessibility QTLs (caQTLs) in each immune cell type and sub-type which identified 6,248 total caQTLs, including those obscured from assays of bulk tissue such as with divergent effects on different cell types. For 3,379 caQTLs we further annotated putative target genes of variant activity using single cell co-accessibility, and caQTL variants were significantly correlated with the accessibility level of linked gene promoters. We fine-mapped loci associated with 16 complex immune traits and identified immune cell caQTLs at 517 candidate causal variants, including those with cell type-specific effects. At the 6q15 locus associated with type 1 diabetes, in line with previous reports, variant rs72928038 was a naive CD4+ T cell caQTL linked to BACH2 and we validated the allelic effects of this variant on regulatory activity in Jurkat T cells. These results highlight the utility of snATAC-seq for mapping genetic effects on accessible chromatin in specific cell types and provide a resource for annotating complex immune trait loci.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Shared and distinct molecular effects of regulatory genetic variants provide insight into mechanisms of distal enhancer-promoter communication 98%
- The influence of HLA genetic variation on plasma protein expression 97%
- COVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types. 96%
Similar papers in this journal
- Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells 98%
- Tissue-specific enhancer-gene maps from multimodal single-cell data identify causal disease alleles 97%
- Linking candidate causal autoimmune variants to T cell networks using genetic and epigenetic screens in primary human T cells. 97%
Similar papers in this journal
- Impact of disease-associated chromatin accessibility QTLs across immune cell types and contexts 98%
- Functional Inference of Gene Regulation using Single-Cell Multi-Omics 98%
- Colocalization of blood cell traits GWAS associations and variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants 98%
Similar papers in this journal
- Chromatin conformation dynamics during CD4+ T cell activation implicates autoimmune disease-associated genes and regulatory elements 98%
- Chromatin accessibility variation provides insights into missing regulation underlying immune-mediated diseases 97%
- RAG suppresses group 2 innate lymphoid cells 96%
Similar papers in this journal
- Genetic effects of sequence-conserved enhancer-like elements on human complex traits 96%
- scDALI: Modelling allelic heterogeneity of DNA accessibility in single-cells reveals context-specific genetic regulation 96%
- Severe COVID-19 associated variants linked to chemokine receptor gene control in monocytes and macrophages 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.