3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility.

Genome-wide association studies (GWAS) have identified genetic links to autoimmune disorders, but lack detail on causal elements. We generated 3D genomic datasets of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq across 57 human cell types integrated with GWAS of 16 autoimmune traits. These data allowed us to map disease-associated variants to their effector genes and identify impacted cell types more effectively than using 1D genomic features or eQTL approaches. Most variants implicated by 3D cis-regulatory architectures are trait-specific, while half the target genes are shared across multiple disorders and cell types, leading to enrichment of similar biological networks. This indicates complex genetic diversity converges on shared targets, yet unique pathways were identified offering avenues for targeted therapies. We pharmacologically validated squalene synthase, a cholesterol biosynthetic enzyme encoded by the