Mapping genetic effects on cell type-specific chromatin accessibility and annotating complex immune trait variants...

Area of Science:

• Genomics
• Immunology
• Molecular Biology

Background:

• Gene regulation is cell type-specific, necessitating high-resolution molecular phenotyping for understanding complex trait variants.
• Non-coding genetic variants' functions require cell type-specific analysis to link them to complex traits.

Purpose of the Study:

• To perform single nucleus ATAC-seq and genotyping to map chromatin accessibility QTLs (caQTLs) in distinct immune cell types.
• To identify cell type-specific genetic variants influencing complex immune traits and annotate their target genes.

Main Methods:

• Single nucleus ATAC-seq (snATAC-seq) and genotyping on peripheral blood mononuclear cells from 13 individuals.
• Clustering of chromatin accessibility profiles to identify 17 immune cell types and sub-types.
• Mapping of caQTLs and annotation of target genes using single-cell co-accessibility.

Main Results:

• Identified 6,901 caQTLs (FDR < .10) and 4,220 caQTLs (FDR < .05) across 17 immune cell types.
• Discovered cell type-specific caQTLs, including variants missed by bulk tissue assays.
• Linked 622 candidate causal variants to 16 complex immune traits, with cell type-specific effects observed.
• Validated a type 1 diabetes-associated variant (rs72928038) affecting BACH2 in naïve CD4+ T cells.

Conclusions:

• Single nucleus ATAC-seq is effective for mapping genetic effects on chromatin accessibility at cell type resolution.
• Identified cell type-specific genetic variants and their regulatory roles in complex immune traits.
• Provides a valuable resource for understanding the genetic architecture of immune regulation.