Genome-wide classification of epigenetic activity reveals regions of enriched in immune-related traits

Epigenetics underpins the regulation of genes known to play a key role in the adaptive and innate immune system (AIIS). We developed a method, EpiNN, that leverages epigenetic data to detect AIIS-relevant genomic regions and used it to detect 2,765 putative AIIS loci. Experimental validation of one of these loci, DNMT1, provided evidence for a novel AIIS-specific transcription start site. We built a genome-wide AIIS annotation and used linkage disequilibrium (LD) score regression to test whether it predicts regional heritability using association statistics for 176 traits. We detected significant heritability effects (average IT*I = 1:65) for 20 out of 26 immune -relevant traits. In a meta -analysis, immune -relevant traits and diseases were 4.453 more enriched for heritability than other traits. The EpiNN annotation was also depleted of transancestry genetic correlation, indicating ancestry -specific effects. These results underscore the effectiveness of leveraging supervised learning algorithms and epigenetic data to detect loci implicated in specific classes of traits and diseases.