Allele-specific genomics decodes gene targets and mechanisms of the non-coding genome

A large proportion of disease variants is found in non-coding RNAs (ncRNAs), gene loci that have been identified as key regulatory elements. However, for most ncRNAs, their targets are unknown, hindering our ability to understand complex diseases. Here, we found that allele-specific ncRNAs were enriched nearby allelic protein-coding genes (pcGenes), suggesting that the allele-specific information could be used to predict cis-acting ncRNA-targets. We translated this concept into the Allelome.LINK framework and applied it to the major mouse organs, revealing 397 events where the allele-specific expression (ASE) of a ncRNA correlated with the ASE of a nearby pcGene, suggesting either enhancing or repressive regulatory interactions. Next, we applied our strategy to the largest human dataset including tissues from nearly 1,000 individuals. Given the outbred nature of humans, each individual allows for the discovery of novel ASE correlation events. We uncovered 2,291 shared ASE events along with their mechanisms, which we benchmarked against sample-matched eQTLs, yielding a high validation rate of 77.47%. Further GWAS integration assigned 30.59% of variants overlapping informative ncRNAs to their pcGene targets. As more sequencing data and risk variants become available, this strategy has the potential to decode the entire cis-acting landscape of the non-coding genome.