Mapping genetic effects on cell type-specific chromatin accessibility and annotating complex immune trait variants using single nucleus ATAC-seq in peripheral blood.

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 13 individuals. Clustering chromatin accessibility profiles of 96,002 total nuclei identified 17 immune cell types and sub-types. We mapped chromatin accessibility QTLs (caQTLs) in each immune cell type and sub-type using individuals of European ancestry which identified 6,901 caQTLs at FDR < .10 and 4,220 caQTLs at FDR < .05, including those obscured from assays of bulk tissue such as with divergent effects on different cell types. For 3,941 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 622 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 naïve 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.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. Gaulton has done consulting for Genentech and holds stock in Neurocrine Biosciences. Dr. Benaglio is an employee of Shoreline Bioscience. Dr. Chiou is an employee and shareholder of Pfizer. These affiliations have no competing interest related to the submitted work. The other authors have no competing interests to disclose. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
(Copyright: © 2023 Benaglio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)