adult human brain (Supplementary Table 7), consistent with the observation that intermediately methylated domains, one potential consequence of allele-specific DNA methylation, are enriched in DHSs25. We also identified a significant enrichment of genotype-associated DNA methylation sites overlapping annotated transcription factor binding sites identified by the ENCODE project10,26 (relative enrichment = 1.26, P = 2.96×10−11) (Supplementary Table 8). Of note, there is a highly-significant enrichment (odds ratio = 1.35, P = 1.66×10−9) of fetal brain mQTLs influencing DNA methylation in CCCTC-binding factor (CTCF) motifs (Supplementary Table 8), confirming a finding from a previous study of heritable DNA methylation sites in the human brain27. CTCF is an 11 zinc-finger protein with insulator and chromatin barrier activity whose binding affinity is known to be strongly influenced by DNA methylation28. Given the important role of CTCF in core genomic processes including transcription, chromosomal interactions and chromatin structure29, the enrichment of genetically-mediated DNA methylation at CTCF binding sites highlights an important potential mechanism linking genetic variation to genomic function. In addition to CTCF, a significant enrichment was also observed within binding sites for several other transcription factors, including IRF1, GABP, ELF1, Rad21 and CCNT2, with significant depletion in binding sites for others (e.g. SUZ12, CtBP2)
