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

A substantial proportion of disease variants reside in non-coding RNAs (ncRNAs), which serve as important regulatory elements. However, most ncRNA targets remain unknown, hindering our understanding of complex diseases. We found allele-specific ncRNAs enriched near allelic protein-coding genes, suggesting that allele-specific expression could be used to predict ncRNA-targets. We applied this concept to mouse organs, revealing 397 enhancing or repressive ncRNA-to-target associations. Next, we applied this strategy to tissues from nearly 1,000 individuals (GTEx). Given the outbred nature of humans, each individual harbors a unique allele-specific landscape, allowing novel ncRNA-to-target discovery with each individual. We uncovered 2,291 ncRNA-to-targets along with their mechanisms, which we benchmarked against sample-matched eQTLs. Further GWAS integration assigned 30.59% of variants overlapping informative ncRNA to their protein-coding targets. As more sequencing data and risk variants become available, this strategy will continue to elucidate targets and mechanisms, ultimately decoding the entire cis-acting landscape of the non-coding genome.