The GATA3 gene is essential for T cell differentiation and is surrounded by risk variants for immune traits. Interpretation of these variants is challenging because the regulatory landscape of GATA3 is complex with dozens of potential enhancers spread across a large topological associating domain (TAD) and gene expression quantitative trait locus (eQTL) studies provide limited evidence for variant function. Here, we perform a tiling deletion screen in Jurkat T cells to identify 23 candidate regulatory elements. Using small deletions in primary T helper 2 (Th2) cells, we validate the function of five of these elements, two of which contain risk variants for asthma and allergic diseases. We fine-map genome-wide association study (GWAS) signals in a distal regulatory element, 1 Mb downstream, to identify 14 candidate causal variants. Small deletions spanning candidate rs725861 decrease GATA3 expression in Th2 cells suggesting a causal mechanism for this variant in allergic diseases. Our study demonstrates the power of integrating GWAS signals with deletion mapping and identifies critical regulatory sequences for GATA3.

The amygdala contributes to negative emotional states associated with relapse to drug seeking, but the cell type-specific gene regulatory programs that are involved in addiction are unknown. Here we generate an atlas of single nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with low and high cocaine addiction-like behaviors following a prolonged period of abstinence. Between rats with different addiction indexes, there are thousands of cell type-specific differentially expressed genes and these are enriched for molecular pathways including GABAergic synapse in astrocytes, excitatory, and somatostatin neurons. We find that rats with higher addiction severity have excessive GABAergic inhibition in the amygdala, and that hyperpolarizing GABAergic transmission and relapse-like behavior are reversed by pharmacological manipulation of the metabolite methylglyoxal, a GABAA receptor agonist. By analyzing chromatin accessibility, we identify thousands of cell type-specific chromatin sites and transcription factor (TF) motifs where accessibility is associated with addiction-like behaviors, most notably at motifs for pioneer TFs in the FOX, SOX, and helix-loop-helix families.

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