Shared and unique 3D genomic features of substance use disorders across multiple cell types.

Recent genome-wide association studies (GWAS) revealed shared genetic components among substance use disorders (SUDs). However, the extent of underlying shared causal variants, effector genes, and cellular contexts, remain unclear. We integrated 3D genomic datasets (high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, RNA-seq) from 59 diverse human cell types with recent GWAS summary statistics for alcohol (AUD), tobacco (TUD), opioid (OUD), and cannabis use disorder (CanUD). Using stratified LD regression, we determined the proportion of SNP heritability attributable to features in these cell types. We observed significant enrichments (<0.05) in 25 cell types. Heritability reached 4.2-fold enrichment for CanUD in iPSC-derived cortical neurons and 6-fold for AUD/TUD in neural progenitors, confirming their relevance for functional exploration. Additionally, pancreatic cell types, notably insulin-secreted beta cells, showed heritability enrichment for TUD (4.8-fold) and CanUD (5.8-fold), suggesting genomic overlap with metabolic processes. Further investigation revealed significant positive genetic correlations between AUD, TUD, and CanUD with type 2 diabetes (T2D) (FDR<0.05). A multi-omic integrated assessment of T2D-SUD correlated loci revealed strong correlations between gene expression and chromatin accessibility at corresponding cis-regulatory elements and shared functional modules. Our study provides new genomic insights into SUDs and implicates specific cell types for targeted functional follow-up to pinpoint causal variant-gene mechanisms.