Mapping functional non-coding variation in individual human genomes through haplotyping, multiomics, and deep learning

Most genetic variants in the human genome reside in non-coding regions, where they can perturb regulatory element activity to influence gene expression, thereby contributing to various phenotypes and diseases. However, identifying functionally relevant non-coding genetic variation remains challenging. Here we integrate personal genomics, allele-specific gene regulation, and deep learning predictions to map the impact of non-coding variation in its native allelic and regulatory context. Leveraging whole-chromosome haplotypes and allele-specific analyses, we establish regulatory links within individual human genomes, enabling us to evaluate functional consequences of both common and rare variants. We identify and validate hundreds of cell-type-specific transcription factor binding events disrupted by genetic variants, revealing known and novel mechanisms that underlie allele-specific chromatin accessibility and gene expression. Using this framework, we discovered a rare variant that disrupted an OCT2 binding site within a distal enhancer, thereby modulating the expression of PIK3R5 gene. Our study establishes a generalisable strategy for interpreting non-coding regulatory variation, enabling systematic dissection of variant effects across diverse biological systems and offering a framework to investigate disease mechanisms.