This study has also revealed novel biological insights for opioid misuse. While we were unable to replicate the previously reported GWAS signals associated with OUD, we discovered two novel loci associated with POU. Rs640561 replicated in the largest available GWAS of OUD ([7]). Both lead SNPs (rs3791033, rs640561) and nearby genes have shown previous associations with other psychiatric traits, particularly smoking phenotypes, which are known to be highly comorbid with OUD and were also strongly correlated with POU. In particular, one of the strongest signals included variants in KDM4A, which is a protein-coding gene that belongs to the Jumonji domain 2 (JMJD2) family of histone demethylases [45]. KDM4 demethylases catalyze the removal of the methyl marks (H3K9me3, H3K36me3), thereby regulating a range of crucial biological functions [46], including cell differentiation and proliferation. Intriguingly, the JMJD2 or KDM4 family have been shown to be important epigenetic regulators in cancer cells [47–49] and, relevant to this study, reward circuitry in depression [50] and alcohol withdrawal [51, 52]. The fact that KDM4A has known interactions with medications that are used to treat other
