Crosstalk between epitranscriptomic and epigenomic modifications and its implication in human diseases.

Crosstalk between N⁶-methyladenosine (m⁶A) and epigenomes is crucial for gene regulation, but its regulatory directionality and disease significance remain unclear. Here, we utilize quantitative trait loci (QTLs) as genetic instruments to delineate directional maps of crosstalk between m⁶A and two epigenomic traits, DNA methylation (DNAme) and H3K27ac. We identify 47 m⁶A-to-H3K27ac and 4,733 m⁶A-to-DNAme and, in the reverse direction, 106 H3K27ac-to-m⁶A and 61,775 DNAme-to-m⁶A regulatory loci, with differential genomic location preference observed for different regulatory directions. Integrating these maps with complex diseases, we prioritize 20 genome-wide association study (GWAS) loci for neuroticism, depression, and narcolepsy in brain; 1,767 variants for asthma and expiratory flow traits in lung; and 249 for coronary artery disease, blood pressure, and pulse rate in muscle. This study establishes disease regulatory paths, such as rs3768410-DNAme-m⁶A-asthma and rs56104944-m⁶A-DNAme-hypertension, uncovering locus-specific crosstalk between m⁶A and epigenomic layers and offering insights into regulatory circuits underlying human diseases.