Context Dependent Perturbation of Allelic Expression Imbalance Reveals Novel Candidate Therapeutic Targets for Metabolic diseases

Background Obesity is a pivotal trigger for a spectrum of complex metabolic disorders. By colocalizing cis-eQTLs in adipose tissues from the GTEx consortium and trait-associated SNPs for complex traits from the GWAS Catalog within 3.6 million DNase I hypersensitive sites (DHSs), we systematically identify regulatory variants and genes that exhibit cis effects, as well as potential causal variants within the context of regulatory elements. Results Our analysis reveals that 229,504 (26.4%) cis-eQTLs located within DHS reside densely near the transcription start sites, contrasting with those outside of DHS. We observed that genes with higher allelic imbalance have shorter transcript lengths with larger number cis-eQTLs within DHS, and such imbalance genes are predominantly linked to signaling and immune response, whereas those with lower allelic imbalance tend to be involved in metabolism. Our composite colocalization score prioritizes 5,202 DHSs that encompass both cis-eQTLs and trait-associated SNPs, targeting 2,232 protein-coding genes and 523 lncRNAs across complex traits. We highlight the lncRNA SNHG5 as a prime example; it is associated with high-density lipoprotein levels and exhibits low allelic imbalance, and is also down-regulated in adipose tissue from patients with obesity. Conclusions Our findings underscore the critical role of regulatory context in pinpointing causal variants and refining target genes, offering rich insights into the genetic mechanisms pertinent to obesity and providing valuable resources for the diagnosis and therapeutic targeting of metabolic diseases. ### Competing Interest Statement The authors have declared no competing interest.