The cAMP pathway is activated by drugs of abuse,(Nestler, 2001) and the protein encoded by KAT2B is a direct regulator of this pathway.(Ravnskjaer et al., 2013) KAT2B promotes transcription activation by inducing epigenetic changes (specifically, increased histone H3K9 acetylation) that enhance the occupancy of promoter binding sites by the CREB protein and its cofactor (CREB regulated transcription coactivator 2, CRTC2), leading to increased expression of target genes.(Ravnskjaer et al., 2013) The CREB protein is bound by another transcriptional regulator, known as CREBBP (or CBP). CREB and CREBBP were recently highlighted in a pathway analysis using GWAS results for opioid dependence.(Gelernter et al., 2013) Our GeneMANIA network drew a biological connection between KAT2B and CREBBP based on their physical interaction, pathways, and shared protein domains, and we found that expression of both genes was down-regulated by the protective allele for drug abuse, rs9829896-C, specifically in AAs. The trans-eQTL pattern between the protective rs9829896-C allele and reduced CREBBP gene expression is consistent with prior indications related to drug-seeking behavior. Mice with CREBBP depleted in the nucleus accumbens show impaired sensitivity and reward
